CN1926114B - Processes for preparing substituted N-aryl-N'-[3-(1H-pyrazol-5-yl) phenyl] ureas and intermediates thereof - Google Patents
Processes for preparing substituted N-aryl-N'-[3-(1H-pyrazol-5-yl) phenyl] ureas and intermediates thereof Download PDFInfo
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- CN1926114B CN1926114B CN2004800425186A CN200480042518A CN1926114B CN 1926114 B CN1926114 B CN 1926114B CN 2004800425186 A CN2004800425186 A CN 2004800425186A CN 200480042518 A CN200480042518 A CN 200480042518A CN 1926114 B CN1926114 B CN 1926114B
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- 0 *C(C(*)=C(*)C(N(c1ccccc1)N)=C(*)CC1=N*C=C1)C1=C=C1 Chemical compound *C(C(*)=C(*)C(N(c1ccccc1)N)=C(*)CC1=N*C=C1)C1=C=C1 0.000 description 11
- UIRUYCKMZZMHFC-SCSAIBSYSA-N C(C1)[C@H]2SC1=C2 Chemical compound C(C1)[C@H]2SC1=C2 UIRUYCKMZZMHFC-SCSAIBSYSA-N 0.000 description 1
- PVDDVVHBZKBOGA-UHFFFAOYSA-N CC(C1CC2)C2=C1S Chemical compound CC(C1CC2)C2=C1S PVDDVVHBZKBOGA-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
- C07C233/42—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
- C07C233/43—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/16—Halogen atoms or nitro radicals
Abstract
The present invention is directed to processes for the preparation of substituted phenylpyrazole ureas of Formula (I), that are useful as 5-HT2A serotonin receptor modulators for the treatment of disease.
Description
Technical field
The present invention relates to prepare the 5-HT that can be used for treating disease
2AThe method that is substituted the phenylpyrazole urea of serotonin receptor modulator.
Background technology
The G protein coupled receptor has the common structural motif.All these acceptors all have 7 sequences that contain 22 to 24 hydrophobic amino acids, and they form 7 α spirals, all cross over cytolemma.Described transbilayer helix in the film outside by uniting at the amino acid chain that between the 4th and the 5th saturating film spiral, has a bigger ring.Mainly another bigger ring of being made up of hydrophilic amino acid is connected with six with transbilayer helix five in the cytolemma inboard.The C-terminal of described acceptor is positioned at cell, and its N-terminal is arranged in ECS.It is believed that described ring and described C-terminal and the G protein-interacting that is connected with six with spiral five.At present, Gq, Gs, Gi and Go are the G albumen of having identified.
Under physiological condition, the G protein coupled receptor is balanced existence between following two kinds of different states or conformation in cytolemma: " outage " state and " activity " state.One inactive acceptor can not be connected to the endocellular transduction passage to cause a biologically.Receptor conformation is changed into active state allows and is connected to transduction pathway and produces a biologically.
By endogenous ligands or external source agonist ligand, an acceptor can be stable under active state.Recent research (for example, including but not limited to, to the modification of receptor amino acid sequence) provides the mode of stablizing described active state conformation except that part.These modes can effectively be stablized described acceptor by the simulation and the effect of the part of described receptors bind.Be called " composition receptor activation " by these stabilizations that do not rely on the mode of part.
(serotonin 5-HT) is the important G protein coupled receptor of a class to serotonin receptor.It is believed that thrombotonin plays an important role in the process relevant with study and memory, sleep, thermoregulation, mood, motor activity, pain, sexual behaviour and aggressive behaviour, appetite, neurodegeneration adjusting and biology rule.Not surprisingly, thrombotonin is not with relevant such as physiopathology situations such as anxiety, depression, obsession, schizophrenia, suicide, autism, migraine, vomiting, alcoholism and neurodegenerative diseases.About the antipsychotic treatment, method concentrates on the serotonin receptor, and the therapeutical agent of these types can be divided into two classes substantially, " typically " and " atypical ".Both all have the antipsychotic effect, but described typical treatment agent also comprises the occurring together property side effect relevant with motorius (the outer syndrome of pyramidal tract, for example lip is moving, tongue jerking movement, shift action or the like).It is believed that these side reactions are with being related with the interactional compound of other acceptor (for example human dopamine D2 acceptor in the nigrostriatum path).Therefore, the atypia treatment is preferable.It is believed that haloperidol is a kind of typical antipsychotic drug, and it is believed that, W-108 is a kind of atypical antipsychotic agents.
Serotonin receptor is divided into 7 subclass, is called 5-HT
1To 5-HT
7These subclass further are divided into a plurality of hypotypes.For example, 5-HT
2Subclass is divided into three kinds of receptor subtype: 5-HT
2A, 5-HT
2BAnd 5-HT
2CHuman 5-HT
2CAcceptor was found first and cloned in 1987, and human 5-HT
2AAcceptor was found first and clones in nineteen ninety.These two kinds of acceptors are considered to the site of action of phantastica.In addition, 5-HT
2AAnd 5-HT
2CThe antagonist of acceptor it is believed that and can be used for treatment depression, anxiety, psychosis and eating disorder.
Complete human 5-HT encodes
1CAcceptor (is known as 5-HT now
2CAcceptor) and complete human 5-HT
2AThe functional cDNA clone's of acceptor separation, evaluation and express and be set forth in United States Patent (USP) the 4th, 985 respectively, No. 352 and the 5th, 661, in No. 012.Report rat 5-HT
2AAnd rat 5-HT
2CThe sudden change of the endogenous form of acceptor can cause the structure activation (5-HT of these acceptors
2A: Casey, people such as C. (1996) Society for Neuroscience Abstracts, 22:699.10,5-HT
2C: Herrick-Davis, K., and Teitler, M. (1996) Society for NeuroscienceAbstracts, 22:699.18; And Herrick-Davis, people such as K. (1997) J.Neurochemistry 69 (3): 1138).
The small-molecule modulators of serotonin receptor has shown that having multiple treatment uses, the arbitrary disease that for example is used for the treatment of above to be listed.Therefore, need preparation can regulate the compound of serotonin receptor at present.Described method and intermediate promptly relate to these needs and other needs.
Summary of the invention
The invention provides preparation formula (I) compound
-wherein the forming member press this paper definition-method, described method comprises:
A) make formula (II) compound
With formula (III) compound
-wherein Z be isocyanato (NCO) or the isocyanato equivalent-react for some time being fit to form under the condition of described formula (I) compound; Or
B) make formula (II) compound and the reagent that produces isocyanato be fit to the formula that forms (IIa) compound
One wherein Y be isocyanato or isocyanato equivalent-condition under react for some time; And make described formula (IIa) compound and formula (IIIa) compound
Under the condition that is fit to formation described formula (I) compound, react for some time.
The present invention further provides the method for preparation formula (II) compound, described method comprises makes formula (IV) compound
-wherein:
Pr is the amido protecting group; And
R
NBe H;
Or Pr and R
NTogether with N atom that they connected form ring amido protecting group-with go to protect reagent under the condition that is fit to formation described formula (II) compound, to react for some time.
The present invention further provides the method for preparation formula (IV) compound, described method comprises makes the formula V compound
Under the condition that is fit to generation described formula (IV) compound, react for some time with halide reagent.
The present invention further provides the method for preparing the formula V compound, described method comprises makes formula (VI) compound
-R wherein
2aAnd R
2bIndependent separately is C
1-4Alkyl-with have formula NH
2NH-R
2Alkyl hydrazine under the condition that be fit to produce the formula V compound, react for some time.
The present invention further provides the method for preparation formula (VI) compound, described method comprises makes formula (VII) compound
Acetal with tool formula (VIII)
-wherein R and R ' are independent separately is C
1-6Alkyl, aralkyl or alkylaryl, or R and R ' form 5-or 6-unit Heterocyclylalkyl-react for some time being fit to produce under the condition of described formula (VI) compound together with the CH base of O atom that they connected and insertion.
The present invention further provides formula (II), (IV), (V) and processing procedure intermediate (VI)
-wherein the forming member is provided by this paper.
Embodiment
The present invention relates to be used to prepare method and the intermediate that is substituted the phenylpyrazole urea, the wherein said phenylpyrazole urea that is substituted can be used as 5-HT
2ASerotonin receptor modulator is used for the treatment of by 5-HT
2ASerotonin receptor is expressed and/or the active illness that mediates, for example central nervous system disorders (as dementia, behavior illness, psychosis, lucky as to draw Tourette syndrome to wait group (Gilles de la Tourette ' s syndrome), manic psychosis, schizophrenia and like that), cardiovascular disorder (as coronary artery disease, myocardial infarction, transient ischemic attack, stenocardia, apoplexy, auricular fibrillation and like that), somnopathy and other illness.
Case method of the present invention and intermediate hereinafter are provided in response diagram Ia and Ib, and the forming member of compound that wherein the present invention illustrates is by hereinafter definition.
Response diagram Ia
In first aspect present invention, provide to comprise formula (I), (II), (IIa), (IIc), (IId), (III), (IIIa), (IV), (IVa), (V), (Vb), (VI), (VIa), (VII), (VIIa) and (VIII) or the method for making of its salt form, as by as illustrated in response diagram Ia and Ib (above) and Ic and the Id (hereinafter).
R
1a, R
1b, R
1c, R
1dAnd R
1eIndependent separately is H, halogen, cyano group, nitro, C
1-6Alkyl, C
1-6Haloalkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, OR
7, SR
7, SOR
8, SO
2R
8, COR
8, COOR
7, OC (O) R
8, NR
9R
10, according to circumstances through one or more R
6The carbocylic radical that replaces or according to circumstances through one or more R
6The heterocyclic radical that replaces; Or R
1aAnd R
1b, R
1bAnd R
1c, R
1cAnd R
1dOr R
1dAnd R
1eForm a C together with the carbon atom that they connected
5-7Cycloalkyl or condense C
5-7Heterocyclylalkyl; Wherein said C
1-6Alkyl, C
2-6Thiazolinyl and C
2-6Alkynyl is separately according to circumstances through one or more C
1-6Acyl group, C
1-6Acyloxy, C
1-6Alkoxyl group, C
1-6Thio alkoxy, carboxylic acid amides, C
1-6Alkyl carboxylic acid amides, C
2-8Dialkyl group carboxylic acid amides, C
1-6Alkyl sulfonamide, C
1-6Alkyl sulphinyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl urea groups, amino, C
1-6Alkylamino, C
2-8Dialkylamino, C
1-6Carbalkoxy, carboxyl, cyano group, C
3-7Cycloalkyl, halogen, C
1-6Halogenated alkoxy, C
1-6Halo thio alkoxy, C
1-6Haloalkyl, C
1-6Haloalkyl sulfinyl, C
1-6Halogenated alkyl sulfonyl, hydroxyl, thin base or nitro replace;
R
2Be C
1-4Alkyl;
R
3Be F, Cl, Br or I;
R
4Be halogen, cyano group, nitro, C
1-6Alkyl, C
1-6Haloalkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkoxyl group, SR
11, SOR
12, SO
2R
12, COR
12, COOR
11, OC (O) R
12, NR
13R
14Or C
3-7Cycloalkyl, wherein said C
1-6Alkoxyl group is according to circumstances through one or more C
1-5Acyl group, C
1-5Acyloxy, C
2-6Thiazolinyl, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-6Alkylamino, C
2-8Dialkylamino, C
1-4Alkyl carboxylic acid amides, C
2-6Alkynyl, C
1-4Alkyl sulfonamide, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Thio alkoxy, C
1-4Alkyl urea groups, amino, (C
1-6Alkoxyl group) carbonyl, carboxylic acid amides, carboxyl, cyano group, C
3-6Cycloalkyl, C
2-6Dialkyl group carboxylic acid amides, halogen, C
1-4Halogenated alkoxy, C
1-4Haloalkyl, C
1-4Haloalkyl sulfinyl, C
1-4Halogenated alkyl sulfonyl, C
1-4Halo thio alkoxy, hydroxyl, nitro or the phenyl that replaces through 1 to 5 halogen atom according to circumstances replace;
R
5When independently occurring is H, halogen, cyano group, nitro, C at every turn
1-6Alkyl, C
1-6Haloalkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkoxyl group, SR
11, SOR
12, SO
2R
12, COR
12, COOR
11, OC (O) R
12, NR
13R
14Or C
3-7Cycloalkyl, wherein said C
1-6Alkoxyl group is according to circumstances through one or more C
1-5Acyl group, C
1-5Acyloxy, C
2-6Thiazolinyl, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-6Alkylamino, C
2-8Dialkylamino, C
1-4Alkyl carboxylic acid amides, C
2-6Alkynyl, C
1-4Alkyl sulfonamide, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Thio alkoxy, C
1-4Alkyl urea groups, amino, (C
1-6Alkoxyl group) carbonyl, carboxylic acid amides, carboxyl, cyano group, C
3-6Cycloalkyl, C
2-6Dialkyl group carboxylic acid amides, halogen, C
1-4Halogenated alkoxy, C
1-4Haloalkyl, C
1-4Haloalkyl sulfinyl, C
1-4Halogenated alkyl sulfonyl, C
1-4Halo thio alkoxy, hydroxyl, nitro or the phenyl that replaces through 1 to 5 halogen atom according to circumstances replace.
R
6Be halogen, cyano group, nitro, C
1-4Alkyl, C
1-4Haloalkyl, C
1-4Alkoxyl group, C
1-4Halogenated alkoxy, amino, (C
1-4Alkyl) amino, two (C
1-4Alkyl) amino, hydroxyl, carboxyl, (C
1-4Alkoxyl group) carbonyl, C
1-4Acyl group, C
1-4Acyloxy, aminocarboxyl, (C
1-4Alkyl) aminocarboxyl or two (C
1-4Alkyl) aminocarboxyl;
R
7And R
11Independent separately is H, C
1-8Alkyl, C
1-8Haloalkyl, C
2-8Thiazolinyl, C
2-8Alkynyl, aryl, heteroaryl, C
3-7Cycloalkyl, 5 to 7 yuan of Heterocyclylalkyls, aralkyl, heteroaralkyl, (C
3-7Cycloalkyl) alkyl or (5 to 7 yuan of Heterocyclylalkyls) alkyl;
R
8And R
12Independent separately is H, C
1-8Alkyl, C
1-8Haloalkyl, C
2-8Thiazolinyl, C
2-8Alkynyl, aryl, heteroaryl, C
3-7Cycloalkyl, 5-7 unit Heterocyclylalkyl, aralkyl, heteroaralkyl, (C
3-7Cycloalkyl) alkyl, (5 to 7 yuan of Heterocyclylalkyls) alkyl, amino, (C
1-4Alkyl) amino or two (C
1-4Alkyl) amino;
R
9And R
10Independent separately is H, C
1-8Alkyl, C
2-8Thiazolinyl, C
2-8Alkynyl, aryl, heteroaryl, C
3-7Cycloalkyl, 5 to 7 yuan of Heterocyclylalkyls, aralkyl, heteroaralkyl, (C
3-7Cycloalkyl) alkyl, (5 to 7 yuan of Heterocyclylalkyls) alkyl, (C
1-8Alkyl) carbonyl, (C
1-8Haloalkyl) carbonyl, (C
1-8Alkoxyl group) carbonyl, (C
1-8Halogenated alkoxy) carbonyl, (C
1-4Alkyl) alkylsulfonyl, (C
1-4Haloalkyl) alkylsulfonyl or aryl sulfonyl;
Or R
9And R
10Form 5 to 7 yuan of Heterocyclylalkyls together with the N atom that they connected;
R
13And R
14Independent separately is H, C
1-8Alkyl, C
2-8Thiazolinyl, C
2-8Alkynyl, aryl, heteroaryl, C
3-7Cycloalkyl, 5 to 7 yuan of Heterocyclylalkyls, aralkyl, heteroaralkyl, (C
3-7Cycloalkyl) alkyl, (5 to 7 yuan of Heterocyclylalkyls) alkyl, (C
1-8Alkyl) carbonyl, (C
1-8Haloalkyl) carbonyl, (C
1-8Alkoxyl group) carbonyl, (C
1-8Halogenated alkoxy) carbonyl, (C
1-4Alkyl) alkylsulfonyl, (C
1-4Haloalkyl) alkylsulfonyl or aryl sulfonyl;
Or R
13And R
14Form 5 to 7 yuan of Heterocyclylalkyls together with the N atom that they connected;
Pr is an amido protecting group;
R
NBe H;
Or Pr and R
NForm a ring amido protecting group together with the N atom that they connected;
R
2aAnd R
2bIndependent separately is C
1-4Alkyl;
R and R ' are independent separately to be C
1-6Alkyl, aralkyl or alkylaryl or R and R ' form a 5-or 6-unit Heterocyclylalkyl together with the CH base of Sauerstoffatom that they connected and insertion;
Y be isocyanato (NCO) or the isocyanato equivalent; And
Z be isocyanato (NCO) or the isocyanato equivalent.
In certain embodiments, R
1a, R
1b, R
1c, R
1dAnd R
1eIndependent separately is H, halogen, cyano group, nitro, C
1-6Alkyl, C
1-6Haloalkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, OR
7, SR
7, SOR
8, SO
2R
8, COR
8, COOR
7, OC (O) R
8, NR
9R
10, according to circumstances through one or more R
6The carbocylic radical that replaces or according to circumstances through one or more R
6The heterocyclic radical that replaces.
Should be appreciated that, when there being an above R
6The time, it can be identical group or different group.
In certain embodiments, R
1a, R
1b, R
1c, R
1dAnd R
1eIndependent separately is H, halogen, cyano group, nitro, C
1-6Alkyl, C
1-6Haloalkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, OR
7Or according to circumstances through one or more R
6The carbocylic radical that replaces.
In certain embodiments, R
1a, R
1b, R
1c, R
1dAnd R
1eIndependent separately is H, halogen, C
1-6Alkyl, C
1-6Haloalkyl, C
1-6Alkyl or C
1-6Haloalkyl.
In certain embodiments, R
1a, R
1b, R
1c, R
1dAnd R
1eIndependent separately is H, F, Cl, Br or I.
In certain embodiments, R
1aBe H or halogen, R
1bBe H, R
1cBe halogen, R
1dBe H, and R
1eBe H.
In certain embodiments, R
1aBe halogen, R
1bBe H, R
1cBe halogen, R
1dBe H, and R
1eBe H.
In certain embodiments:
R
1aBe F, R
1bBe H, R
1cBe F, R
1dBe H, and R
1eBe H;
R
1aBe H, R
1bBe H, R
1cBe Cl, R
1dBe H, and R
1eBe H;
R
1aBe H, R
1bBe H, R
1cBe F, R
1dBe H, and R
1eBe H; Or
R
1aBe H, R
1bBe H, R
1cBe Cl, R
1dBe H, and R
1eBe H.
In certain embodiments, R
2Be methyl or ethyl.
In certain embodiments, R
2Be methyl.
In certain embodiments, R
3Be Cl or Br.
In certain embodiments, R
3Be Br.
In certain embodiments, R
4Be halogen, cyano group, nitro, C
1-6Alkyl, C
1-6Haloalkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkoxyl group, wherein said C
1-6Alkoxyl group is according to circumstances through one or more C
1-5Acyl group, C
1-5Acyloxy, C
2-6Thiazolinyl, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-6Alkylamino, C
2-8Dialkylamino, C
1-4Alkyl carboxylic acid amides, C
2-6Alkynyl, C
1-4Alkyl sulfonamide, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Thio alkoxy, C
1-4Alkyl urea groups, amino, (C
1-6Alkoxyl group) carbonyl, carboxylic acid amides, carboxyl, cyano group, C
3-6Cycloalkyl, C
2-6Dialkyl group carboxylic acid amides, halogen, C
1-4Halogenated alkoxy, C
1-4Haloalkyl, C
1-4Haloalkyl sulfinyl, C
1-4Halogenated alkyl sulfonyl, C
1-4Halo thio alkoxy, hydroxyl, nitro or the phenyl that replaces through 1 to 5 halogen atom according to circumstances replace.
In certain embodiments, R
4For according to circumstances through one or more C
1-5Acyl group, C
1-5Acyloxy, C
2-6Thiazolinyl, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-6Alkylamino, C
2-8Dialkylamino, C
1-4Alkyl carboxylic acid amides, C
2-6Alkynyl, C
1-4Alkyl sulfonamide, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Thio alkoxy, C
1-4Alkyl urea groups, amino, (C
1-6Alkoxyl group) carbonyl, carboxylic acid amides, carboxyl, cyano group, C
3-6Cycloalkyl, C
2-6Dialkyl group carboxylic acid amides, halogen, C
1-4Halogenated alkoxy, C
1-4Haloalkyl, C
1-4Haloalkyl sulfinyl, C
1-4Halogenated alkyl sulfonyl, C
1-4The C that halo thio alkoxy, hydroxyl, nitro or the phenyl that replaces through 1 to 5 halogen atom according to circumstances replace
1-6Alkoxyl group.
In certain embodiments, R
4Be C
1-6Alkoxyl group.
In certain embodiments, R
4Be C
1-3Alkoxyl group.
In certain embodiments, R
4Be methoxy or ethoxy.
In certain embodiments, R
4Be methoxyl group.
In certain embodiments, R
5When independently occurring is H, halogen, cyano group, nitro, C at every turn
1-6Alkyl, C
1-6Haloalkyl, C
2-6Thiazolinyl, C
2-6Alkynyl or C
1-6Alkoxyl group.
In certain embodiments, R
5When independently occurring is H or halogen at every turn.
In certain embodiments, R
5When occurring H at every turn.
In certain embodiments, R and R ' are all C
1-4Alkyl.
In certain embodiments, R and R ' are all methyl.
In certain embodiments, R
2aAnd R
2bBe all methyl.
In certain embodiments, Pr is an acyl group.
In certain embodiments, Pr is-C (O) (C
1-4Alkyl).
In certain embodiments, Pr is-C (O) Me.
In certain embodiments:
R
1a, R
1b, R
1c, R
1dAnd R
1eIndependent separately is H, halogen, cyano group, nitro, C
1-6Alkyl, C
1-6Haloalkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, OR
7, SR
7, SOR
8, SO
2R
8, COR
8, COOR
7, OC (O) R
8, NR
9R
10, according to circumstances through one or more R
6The carbocylic radical that replaces or according to circumstances through one or more R
6The heterocyclic radical that replaces;
R
3Be F, Cl, Br or I;
R
4Be halogen, cyano group, nitro, C
1-6Alkyl, C
1-6Haloalkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkoxyl group, wherein said C
1-6Alkoxyl group is according to circumstances through one or more C
1-5Acyl group, C
1-5Acyloxy, C
2-6Thiazolinyl, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-6Alkylamino, C
2-8Dialkylamino, C
1-4Alkyl carboxylic acid amides, C
2-6Alkynyl, C
1-4Alkyl sulfonamide, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Thio alkoxy, C
1-4Alkyl urea groups, amino, (C
1-6Alkoxyl group) carbonyl, carboxylic acid amides, carboxyl, cyano group, C
3-6Cycloalkyl, C
2-6Dialkyl group carboxylic acid amides, halogen, C
1-4Halogenated alkoxy, C
1-4Haloalkyl, C
1-4Haloalkyl sulfinyl, C
1-4Halogenated alkyl sulfonyl, C
1-4Halo thio alkoxy, hydroxyl, nitro or the phenyl that replaces through 1 to 5 halogen atom according to circumstances replace; And
R
5When independently occurring is H, halogen, cyano group, nitro, C at every turn
1-6Alkyl, C
1-6Haloalkyl, C
2-6Thiazolinyl, C
2-6Alkynyl or C
1-6Alkoxyl group.
In certain embodiments:
R
1a, R
1b, R
1c, R
1dAnd R
1eIndependent separately is H, halogen, C
1-6Alkyl, C
1-6Haloalkyl, C
1-6Alkyl or C
1-6Haloalkyl;
R
3Be F, Cl, Br or I;
R
4For according to circumstances through one or more C
1-5Acyl group, C
1-5Acyloxy, C
2-6Thiazolinyl, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-4Alkylamino, C
2-8Dialkylamino, C
1-4Alkyl carboxylic acid amides, C
2-6Alkynyl, C
1-4Alkyl sulfonamide, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Thio alkoxy, C
1-4Alkyl urea groups, amino, (C
1-6Alkoxyl group) carbonyl, carboxylic acid amides, carboxyl, cyano group, C
3-6Cycloalkyl, C
2-6Dialkyl group carboxylic acid amides, halogen, C
1-4Halogenated alkoxy, C
1-4Haloalkyl, C
1-4Haloalkyl sulfinyl, C
1-4Halogenated alkyl sulfonyl, C
1-4The C that halo thio alkoxy, hydroxyl, nitro or the phenyl that replaces through 1 to 5 halogen atom according to circumstances replace
1-6Alkoxyl group; And
R
5When occurring H at every turn.
In certain embodiments:
R
1a, R
1b, R
1c, R
1dAnd R
1eIndependent separately is H, F, Cl, Br or I;
R
2Be methyl or ethyl;
R
3Be F, Cl, Br or I;
R
4Be C
1-6Alkoxyl group; And
R
5When occurring H at every turn.
In certain embodiments:
R
1a, R
1b, R
1c, R
1dAnd R
1eIndependent separately is H, F or Cl;
R
2Be methyl;
R
3Be Cl or Br;
R
4Be methoxyl group; And
R
5When occurring H at every turn.
In certain embodiments:
R
1aBe F;
R
1bBe H;
R
1cBe F;
R
1dBe H;
R
1eBe H;
R
2Be methyl;
R
3Be Br;
R
4Be methoxyl group; And
R
5When occurring H at every turn.
In certain embodiments:
R
1aBe H;
R
1bBe H;
R
1cBe Cl;
R
1dBe H;
R
1eBe H;
R
2Be methyl;
R
3Be Br;
R
4Be methoxyl group; And
R
5When occurring H at every turn.
In certain embodiments:
R
1aBe H;
R
1bBe H;
R
1cBe F;
R
1dBe H;
R
1eBe H;
R
2Be methyl;
R
3Be Br;
R
4Be methoxyl group; And
R
5When occurring H at every turn.
In certain embodiments:
R
1aBe H;
R
1bBe H;
R
1cBe Cl;
R
1dBe H;
R
1eBe H;
R
2Be methyl;
R
3Be Cl;
R
4Be methoxyl group; And
R
5When occurring H at every turn.
In certain embodiments, Z is-NCO.
In certain embodiments, Y is-NCO.
In certain embodiments:
R
3Be F, Cl, Br or I;
R
4Be halogen, cyano group, nitro, C
1-6Alkyl, C
1-6Haloalkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkoxyl group, wherein said C
1-6Alkoxyl group is according to circumstances through one or more C
1-5Acyl group, C
1-5Acyloxy, C
2-6Thiazolinyl, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-6Alkylamino, C
2-8Dialkylamino, C
1-4Alkyl carboxylic acid amides, C
2-6Alkynyl, C
1-4Alkyl sulfonamide, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Thio alkoxy, C
1-4Alkyl urea groups, amino, (C
1-6Alkoxyl group) carbonyl, carboxylic acid amides, carboxyl, cyano group, C
3-6Cycloalkyl, C
2-6Dialkyl group carboxylic acid amides, halogen, C
1-4Halogenated alkoxy, C
1-4Haloalkyl, C
1-4Haloalkyl sulfinyl, C
1-4Halogenated alkyl sulfonyl, C
1-4Halo thio alkoxy, hydroxyl, nitro or the phenyl that replaces through 1 to 5 halogen atom according to circumstances replace; And
R
5Be H, halogen, cyano group, nitro, C
1-6Alkyl, C
1-6Haloalkyl, C
2-6Thiazolinyl, C
2-6Alkynyl or C
1-6Alkoxyl group.
In certain embodiments:
R
3Be F, Cl, Br or I;
R
4For according to circumstances through one or more C
1-5Acyl group, C
1-5Acyloxy, C
2-6Thiazolinyl, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-6Alkylamino, C
2-8Dialkylamino, C
1-4Alkyl carboxylic acid amides, C
2-6Alkynyl, C
1-4Alkyl sulfonamide, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Thio alkoxy, C
1-4Alkyl urea groups, amino, (C
1-6Alkoxyl group) carbonyl, carboxylic acid amides, carboxyl, cyano group, C
3-6Cycloalkyl, C
2-6Dialkyl group carboxylic acid amides, halogen, C
1-4Halogenated alkoxy, C
1-4Haloalkyl, C
1-4Haloalkyl sulfinyl, C
1-4Halogenated alkyl sulfonyl, C
1-4The C that halo thio alkoxy, hydroxyl, nitro or the phenyl that replaces through 1 to 5 halogen atom according to circumstances replace
1-6Alkoxyl group; And
R
5When occurring H at every turn.
In certain embodiments:
R
2Be methyl or ethyl;
R
3Be F, Cl, Br or I;
R
4Be C
1-6Alkoxyl group; And
R
5When occurring H at every turn.
In certain embodiments:
R
2Be methyl;
R
3Be Cl or Br;
R
4Be methoxyl group; And
R
5When occurring H at every turn.
In certain embodiments, for formula (II) compound, R
2Be methyl; R
3Be Cl or Br; R
4Be methoxyl group; And R
5When occurring H at every turn.
In certain embodiments, for formula (II) compound, R
2Be methyl; R
3Be Br; R
4Be methoxyl group; And R
5When occurring H at every turn.
In certain embodiments, for formula (II) compound, R
2Be methyl; R
3Be Cl; R
4Be methoxyl group; And R
5When occurring H at every turn.
In certain embodiments, for formula (IV) compound, R
2Be methyl; R
3Be Br; R
4Be methoxyl group; R
5When occurring H at every turn; And Pr is-C (O) Me.
In certain embodiments, for formula (IV) compound, R
2Be methyl; R
3Be Cl; R
4Be methoxyl group; R
5When occurring H at every turn; And Pr is-C (O) Me.
In certain embodiments, for the formula V compound, R
2Be methyl; R
4Be methoxyl group; R
5When occurring H at every turn; And Pr is-C (O) Me.
In certain embodiments, for formula (VI) compound, R
2aBe methyl; R
2bBe methyl; R
4Be methoxyl group; R
5When occurring H at every turn; And Pr is-C (O) Me.
Other case method of the present invention and intermediate are provided among response diagram Ic and the Id below, and wherein the forming member of compound that this paper illustrates defines in above reaching hereinafter in this disclosure.
Response diagram Ic
Certain embodiments of the invention for example provide illustrated formula (Ia), (IIc), (IId), (III), (IIIa), (IVa), (Vb), (VIa), (VIIa) and (VIII) processing procedure of compound or its salt form of relating to by response diagram Ic and Id, wherein:
R
1a, R
1b, R
1c, R
1dAnd R
1eIndependent separately is H, halogen, cyano group, nitro, C
1-6Alkyl, C
1-6Haloalkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, OR
7, SR
7, SOR
8, SO
2R
8, COR
8, COOR
7, OC (O) R
8, NR
9R
10, according to circumstances through one or more R
6The carbocylic radical that replaces or according to circumstances through one or more R
6The heterocyclic radical that replaces; Or R
1aAnd R
1b, R
4bAnd R
1c, R
1cAnd R
1dOr R
1dAnd R
1eCondense C together with the carbon atom formation that they connected
5-7Cycloalkyl or condense C
5-7Heterocyclylalkyl; Wherein said C
1-6Alkyl, C
2-6Thiazolinyl and C
2-6Alkynyl is separately according to circumstances through one or more C
1-6Acyl group, C
1-6Acyloxy, C
1-6Alkoxyl group, C
1-6Thio alkoxy, carboxylic acid amides, C
1-6Alkyl carboxylic acid amides, C
2-8Dialkyl group carboxylic acid amides, C
1-6Alkyl sulfonamide, C
1-6Alkyl sulphinyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl urea groups, amino, C
1-6Alkylamino, C
2-8Dialkylamino, C
1-6Carbalkoxy, carboxyl, cyano group, C
3-7Cycloalkyl, halogen, C
1-6Halogenated alkoxy, C
1-6Halo thio alkoxy, C
1-6Haloalkyl, C
1-6Haloalkyl sulfinyl, C
1-6Halogenated alkyl sulfonyl, hydroxyl, sulfydryl or nitro replace;
R
2Be C
1-4Alkyl;
R
3Be F, Cl, Br or I;
R
4Be halogen, cyano group, nitro, C
1-6Alkyl, C
1-6Haloalkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkoxyl group, SR
11, SOR
12, SO
2R
12, COR
12, COOR
11, OC (O) R
12, NR
13R
14Or C
3-7Cycloalkyl, wherein said C
1-6Alkoxyl group is according to circumstances through one or more C
1-5Acyl group, C
1-5Acyloxy, C
2-6Thiazolinyl, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-6Alkylamino, C
2-8Dialkylamino, C
1-4Alkyl carboxylic acid amides, C
2-6Alkynyl, C
1-4Alkyl sulfonamide, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Thio alkoxy, C
1-4Alkyl urea groups, amino, (C
1-6Alkoxyl group) carbonyl, carboxylic acid amides, carboxyl, cyano group, C
3-6Cycloalkyl, C
2-6Dialkyl group carboxylic acid amides, halogen, C
1-4Halogenated alkoxy, C
1-4Haloalkyl, C
1-4Haloalkyl sulfinyl, C
1-4Halogenated alkyl sulfonyl, C
1-4Halo thio alkoxy, hydroxyl, nitro or the phenyl that replaces through 1 to 5 halogen atom according to circumstances replace;
R
5Be H, halogen, cyano group, nitro, C
1-6Alkyl, C
1-6Haloalkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkoxyl group, SR
11, SOR
12, SO
2R
12, COR
12, COOR
11, OC (O) R
12, NR
13R
14Or C
3-7Cycloalkyl, wherein said C
1-6Alkoxyl group is according to circumstances through one or more C
1-5Acyl group, C
1-5Acyloxy, C
2-6Thiazolinyl, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-6Alkylamino, C
2-8Dialkylamino, C
1-4Alkyl carboxylic acid amides, C
2-6Alkynyl, C
1-4Alkyl sulfonamide, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Thio alkoxy, C
1-4Alkyl urea groups, amino, (C
1-6Alkoxyl group) carbonyl, carboxylic acid amides, carboxyl, cyano group, C
3-6Cycloalkyl, C
2-6Dialkyl group carboxylic acid amides, halogen, C
1-4Halogenated alkoxy, C
1-4Haloalkyl, C
1-4Haloalkyl sulfinyl, C
1-4Halogenated alkyl sulfonyl, C
1-4Halo thio alkoxy, hydroxyl, nitro or the phenyl that replaces through 1 to 5 halogen atom according to circumstances replace;
R
6Be halogen, cyano group, nitro, C
1-4Alkyl, C
1-4Haloalkyl, C
1-4Alkoxyl group, C
1-4Halogenated alkoxy, amino, (C
1-4Alkyl) amino, two (C
1-4Alkyl) amino, hydroxyl, carboxyl, (C
1-4Alkoxyl group) carbonyl, C
1-4Acyl group, C
1-4Acyloxy, aminocarboxyl, (C
1-4Alkyl) aminocarboxyl or two (C
1-4Alkyl) aminocarboxyl;
R
7And R
11Independent separately is H, C
1-8Alkyl, C
1-8Haloalkyl, C
2-8Thiazolinyl, C
2-8Alkynyl, aryl, heteroaryl, C
3-7Cycloalkyl, 5 to 7 yuan of Heterocyclylalkyls, aralkyl, heteroaralkyl, (C
3-7Cycloalkyl) alkyl or (5 to 7 yuan of Heterocyclylalkyls) alkyl;
R
8And R
12Independent separately is H, C
1-8Alkyl, C
1-8Haloalkyl, C
2-8Thiazolinyl, C
2-8Alkynyl, aryl, heteroaryl, C
3-7Cycloalkyl, 5 to 7 yuan of Heterocyclylalkyls, aralkyl, heteroaralkyl, (C
3-7Cycloalkyl) alkyl, (5 to 7 yuan of Heterocyclylalkyls) alkyl, amino, (C
1-4Alkyl) amino or two (C
1-4Alkyl) amino;
R
9And R
10Independent separately is H, C
1-8Alkyl, C
2-8Thiazolinyl, C
2-8Alkynyl, aryl, heteroaryl, C
3-7Cycloalkyl, 5 to 7 yuan of Heterocyclylalkyls, aralkyl, heteroaralkyl, (C
3-7Cycloalkyl) alkyl, (5 to 7 yuan of Heterocyclylalkyls) alkyl, (C
1-8Alkyl) carbonyl, (C
1-8Haloalkyl) carbonyl, (C
1-8Alkoxyl group) carbonyl, (C
1-8Halogenated alkoxy) carbonyl, (C
1-4Alkyl) alkylsulfonyl, (C
1-4Haloalkyl) alkylsulfonyl or aryl sulfonyl;
Or R
9And R
10Form 5 to 7 yuan of Heterocyclylalkyls together with the N atom that they connected;
R
13And R
14Independent separately is H, C
1-8Alkyl, C
2-8Thiazolinyl, C
2-8Alkynyl, aryl, heteroaryl, C
3-7Cycloalkyl, 5 to 7 yuan of Heterocyclylalkyls, aralkyl, heteroaralkyl, (C
3-7Cycloalkyl) alkyl, (5 to 7 yuan of Heterocyclylalkyls) alkyl, (C
1-8Alkyl) carbonyl, (C
1-8Haloalkyl) carbonyl, (C
1-8Alkoxyl group) carbonyl, (C
1-8Halogenated alkoxy) carbonyl, (C
1-4Alkyl) alkylsulfonyl, (C
1-4Haloalkyl) alkylsulfonyl or aryl sulfonyl;
Or R
13And R
14Form 5 to 7 yuan of Heterocyclylalkyls together with the N atom that they connected;
Pr is an amido protecting group;
R
NBe H;
Or Pr and R
NForm a ring amido protecting group together with the N atom that they connected;
R
2aAnd R
2bIndependent separately is C
1-4Alkyl;
R and R ' are independent separately to be C
1-6Alkyl, aralkyl or alkylaryl or R and R ' form 5-or 6-unit Heterocyclylalkyl together with the CH base of Sauerstoffatom that they connected and insertion;
Y be isocyanato (NCO) or the isocyanato equivalent; And
Z be isocyanato (NCO) or the isocyanato equivalent.
In certain embodiments, R
1a, R
1b, R
1c, R
1dAnd R
1eIndependent separately is H, halogen, cyano group, nitro, C
1-6Alkyl, C
1-6Haloalkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, OR
7, SR
7, SOR
8, SO
2R
8, COR
8, COOR
7, OC (O) R
8, NR
9R
10, according to circumstances through one or more R
6The carbocylic radical that replaces or according to circumstances through one or more R
6The heterocyclic radical that replaces.
In certain embodiments, R
1a, R
1b, R
1c, R
1dAnd R
1eIndependent separately is H, halogen, cyano group, nitro, C
1-6Alkyl, C
1-6Haloalkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, OR
7Or according to circumstances through one or more R
6The carbocylic radical that replaces.
In certain embodiments, R
1a, R
1b, R
1c, R
1dAnd R
1eIndependent separately is H, halogen, C
1-6Alkyl, C
1-6Haloalkyl, C
1-6Alkyl or C
1-6Haloalkyl.
In certain embodiments, R
1a, R
1b, R
1c, R
1dAnd R
1eIndependent separately is H, F, Cl, Br or I.
In certain embodiments, R
1aBe H or halogen, R
1bBe H, R
1cBe halogen, R
1dBe H, and R
1eBe H.
In certain embodiments, R
1aBe halogen, R
1bBe H, R
1cBe halogen, R
1dBe H, and R
1eBe H.
In certain embodiments:
R
1aBe F, R
1bBe H, R
1cBe F, R
1dBe H, and R
1eBe H;
R
1aBe H, R
1bBe H, R
1cBe Cl, R
D1Be H, and R
1eBe H;
R
1aBe H, R
1bBe H, R
1cBe F, R
1dBe H, and R
1eBe H; Or
R
1aBe H, R
1bBe H, R
1cBe Cl, R
1dBe H, and R
1eBe H.
In certain embodiments, R
2Be methyl or ethyl.
In certain embodiments, R
2Be methyl.
In certain embodiments, R
3Be Cl or Br.
In certain embodiments, R
3Be Br.
In certain embodiments, R
4Be halogen, cyano group, nitro, C
1-6Alkyl, C
1-6Haloalkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkoxyl group, wherein said C
1-6Alkoxyl group is according to circumstances through one or more C
1-5Acyl group, C
1-5Acyloxy, C
2-6Thiazolinyl, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-6Alkylamino, C
2-8Dialkylamino, C
1-4Alkyl carboxylic acid amides, C
2-6Alkynyl, C
1-4Alkyl sulfonamide, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Thio alkoxy, C
1-4Alkyl urea groups, amino, (C
1-6Alkoxyl group) carbonyl, carboxylic acid amides, carboxyl, cyano group, C
3-6Cycloalkyl, C
2-6Dialkyl group carboxylic acid amides, halogen, C
1-4Halogenated alkoxy, C
1-4Haloalkyl, C
1-4Haloalkyl sulfinyl, C
1-4Halogenated alkyl sulfonyl, C
1-4Halo thio alkoxy, hydroxyl, nitro or the phenyl that replaces through 1 to 5 halogen atom according to circumstances replace.
In certain embodiments, R
4For according to circumstances through one or more C
1-5Acyl group, C
1-5Acyloxy, C
2-6Thiazolinyl, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-6Alkylamino, C
2-8Dialkylamino, C
1-4Alkyl carboxylic acid amides, C
2-6Alkynyl, C
1-4Alkyl sulfonamide, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Thio alkoxy, C
1-4Alkyl urea groups, amino, (C
1-6Alkoxyl group) carbonyl, carboxylic acid amides, carboxyl, cyano group, C
3-6Cycloalkyl, C
2-6Dialkyl group carboxylic acid amides, halogen, C
1-4Halogenated alkoxy, C
1-4Haloalkyl, C
1-4Haloalkyl sulfinyl, C
1-4Halogenated alkyl sulfonyl, C
1-4The C that halo thio alkoxy, hydroxyl, nitro or the phenyl that replaces through 1 to 5 halogen atom according to circumstances replace
1-6Alkoxyl group.
In certain embodiments, R
4Be C
1-6Alkoxyl group.
In certain embodiments, R
4Be C
1-3Alkoxyl group.
In certain embodiments, R
4Be methoxy or ethoxy.
In certain embodiments, R
4Be methoxyl group.
In certain embodiments, R
5Be H, halogen, cyano group, nitro, C
1-6Alkyl, C
1-6Haloalkyl, C
2-6Thiazolinyl, C
2-6Alkynyl or C
1-6Alkoxyl group.
In certain embodiments, R
5Be H.
In certain embodiments, R and R ' are all C
1-4Alkyl.
In certain embodiments, R and R ' are all methyl.
In certain embodiments, R
2aAnd R
2bBe all methyl.
In certain embodiments, Pr is an acyl group.
In certain embodiments, Pr is-C (O) (C
1-4Alkyl).
In certain embodiments, Pr is-C (O) Me.
In certain embodiments:
R
1a, R
1b, R
1c, R
1dAnd R
1eIndependent separately is H, halogen, cyano group, nitro, C
1-6Alkyl, C
1-6Haloalkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, OR
7, SR
7, SOR
8, SO
2R
8, COR
8, COOR
7, OC (O) R
8, NR
9R
10, according to circumstances through one or more R
6The carbocylic radical that replaces or according to circumstances through one or more R
6The heterocyclic radical that replaces;
R
3Be F, Cl, Br or I;
R
4Be halogen, cyano group, nitro, C
1-6Alkyl, C
1-6Haloalkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkoxyl group, wherein said C
1-6Alkoxyl group is according to circumstances through one or more C
1-5Acyl group, C
1-5Acyloxy, C
2-6Thiazolinyl, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-6Alkylamino, C
2-8Dialkylamino, C
1-4Alkyl carboxylic acid amides, C
2-6Alkynyl, C
1-4Alkyl sulfonamide, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Thio alkoxy, C
1-4Alkyl urea groups, amino, (C
1-6Alkoxyl group) carbonyl, carboxylic acid amides, carboxyl, cyano group, C
3-6Cycloalkyl, C
2-6Dialkyl group carboxylic acid amides, halogen, C
1-4Halogenated alkoxy, C
1-4Haloalkyl, C
1-4Haloalkyl sulfinyl, C
1-4Halogenated alkyl sulfonyl, C
1-4Halo thio alkoxy, hydroxyl, nitro or the phenyl that replaces through 1 to 5 halogen atom according to circumstances replace; And
R
5Be H, halogen, cyano group, nitro, C
1-6Alkyl, C
1-6Haloalkyl, C
2-6Thiazolinyl, C
2-6Alkynyl or C
1-6Alkoxyl group.
In certain embodiments:
R
1a, R
1b, R
1c, R
1dAnd R
1eIndependent separately is H, halogen, C
1-6Alkyl, C
1-6Haloalkyl, C
1-6Alkyl or C
1-6Haloalkyl;
R
3Be F, Cl, Br or I;
R
4For according to circumstances through one or more C
1-5Acyl group, C
1-5Acyloxy, C
2-6Thiazolinyl, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-6Alkylamino, C
2-8Dialkylamino, C
1-4Alkyl carboxylic acid amides, C
2-6Alkynyl, C
1-4Alkyl sulfonamide, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Thio alkoxy, C
1-4Alkyl urea groups, amino, (C
1-6Alkoxyl group) carbonyl, carboxylic acid amides, carboxyl, cyano group, C
3-6Cycloalkyl, C
2-6Dialkyl group carboxylic acid amides, halogen, C
1-4Halogenated alkoxy, C
1-4Haloalkyl, C
1-4Haloalkyl sulfinyl, C
1-4Halogenated alkyl sulfonyl, C
1-4The C that halo thio alkoxy, hydroxyl, nitro or the phenyl that replaces through 1 to 5 halogen atom according to circumstances replace
1-6Alkoxyl group; And
R
5Be H.
In certain embodiments:
R
1a, R
1b, R
1c, R
1dAnd R
1eIndependent separately is H, F, Cl, Br or I;
R
2Be methyl or ethyl;
R
3Be F, Cl, Br or I;
R
4Be C
1-6Alkoxyl group;
And R
5Be H.
In certain embodiments:
R
1a, R
1b, R
1c, R
1dAnd R
1eIndependent separately is H, F or Cl;
R
2Be methyl;
R
3Be Cl or Br;
R
4Be methoxyl group; And
R
5Be H.
In certain embodiments:
R
1aBe F;
R
1bBe H;
R
1cBe F;
R
1dBe H;
R
1eBe H;
R
2Be methyl;
R
3Be Br;
R
4Be methoxyl group; And
R
5Be H.
In certain embodiments:
R
1aBe H;
R
1bBe H;
R
1cBe Cl;
R
1dBe H;
R
1eBe H;
R
2Be methyl;
R
3Be Br;
R
4Be methoxyl group; And
R
5Be H.
In certain embodiments:
R
1aBe H;
R
1bBe H;
R
1cBe F;
R
1dBe H;
R
1eBe H;
R
2Be methyl;
R
3Be Br;
R
4Be methoxyl group; And
R
5Be H.
In certain embodiments:
R
1aBe H;
R
1bBe H;
R
1cBe Cl;
R
1dBe H;
R
1eBe H;
R
2Be methyl;
R
3Be Cl;
R
4Be methoxyl group; And
R
5Be H.
In certain embodiments, Z is-NCO.
In certain embodiments, Y is-NCO.
In certain embodiments:
R
3Be F, Cl, Br or I;
R
4Be halogen, cyano group, nitro, C
1-6Alkyl, C
1-6Haloalkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkoxyl group, wherein said C
1-6Alkoxyl group is according to circumstances through one or more C
1-5Acyl group, C
1-5Acyloxy, C
2-6Thiazolinyl, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-6Alkylamino, C
2-8Dialkylamino, C
1-4Alkyl carboxylic acid amides, C
2-6Alkynyl, C
1-4Alkyl sulfonamide, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Thio alkoxy, C
1-4Alkyl urea groups, amino, (C
1-6Alkoxyl group) carbonyl, carboxylic acid amides, carboxyl, cyano group, C
3-6Cycloalkyl, C
2-6Dialkyl group carboxylic acid amides, halogen, C
1-4Halogenated alkoxy, C
1-4Haloalkyl, C
1-4Haloalkyl sulfinyl, C
1-4Halogenated alkyl sulfonyl, C
1-4Halo thio alkoxy, hydroxyl, nitro or the phenyl that replaces through 1 to 5 halogen atom according to circumstances replace; And
R
5Be H, halogen, cyano group, nitro, C
1-6Alkyl, C
1-6Haloalkyl, C
2-6Thiazolinyl, C
2-6Alkynyl or C
1-6Alkoxyl group.
In certain embodiments:
R
3Be F, Cl, Br or I;
R
4For according to circumstances through one or more C
1-5Acyl group, C
1-5Acyloxy, C
2-6Thiazolinyl, C
1-4Alkoxyl group, C
1-8Alkyl, C
1-6Alkylamino, C
2-8Dialkylamino, C
1-4Alkyl carboxylic acid amides, C
2-6Alkynyl, C
1-4Alkyl sulfonamide, C
1-4Alkyl sulphinyl, C
1-4Alkyl sulphonyl, C
1-4Thio alkoxy, C
1-4Alkyl urea groups, amino, (C
1-6Alkoxyl group) carbonyl, carboxylic acid amides, carboxyl, cyano group, C
3-6Cycloalkyl, C
2-6Dialkyl group carboxylic acid amides, halogen, C
1-4Halogenated alkoxy, C
1-4Haloalkyl, C
1-4Haloalkyl sulfinyl, C
1-4Halogenated alkyl sulfonyl, C
1-4The C that halo thio alkoxy, hydroxyl, nitro or the phenyl that replaces through 1 to 5 halogen atom according to circumstances replace
1-6Alkoxyl group; And
R
5Be H.
In certain embodiments:
R
2Be methyl or ethyl;
R
3Be F, C1, Br or I;
R
4Be C
1-6Alkoxyl group; And
R
5Be H.
In certain embodiments:
R
2Be methyl;
R
3Be Cl or Br;
R
4Be methoxyl group; And
R
5Be H.
In certain embodiments, for formula (IIc) compound, R
2Be methyl; R
3Be Cl or Br; R
4Be methoxyl group; And R
5Be H.
In certain embodiments, for formula (IVa) compound, R
2Be methyl; R
3Be Br; R
4Be methoxyl group; R
5Be H; And Pr is-C (O) Me.
In certain embodiments, for formula (IVa) compound, R
2Be methyl; R
3Be Cl; R
4Be methoxyl group; R
5Be H; And Pr is-C (O) Me.
In certain embodiments, for formula (Vb) compound, R
2Be methyl; R
4Be methoxyl group; R
5Be H; And Pr is-C (O) Me.
In certain embodiments, for formula (VIa) compound, R
2aBe methyl; R
2bBe methyl; R
4Be methoxyl group; R
5Be H; And Pr is-C (O) Me.
Urea forms step
But production (I) compound and form the chemical reaction of urea key can be by any enforcement in the known several different methods in the industry.Exemplary urea forming process of the present invention is illustrated among response diagram Ia and the Ic.
Therefore, following formula: compound (I)
-wherein the forming member define-can pass through by this paper: make (II) compound
With the same form (III) compound
-wherein Z be isocyanato (NCO) or the isocyanato equivalent-under the condition that is fit to the formula that forms (I) compound, react for some time; Or
Make formula (II) compound and the reagent that produces isocyanato be fit to the formula that forms (IIa) compound
-wherein Y be isocyanato or isocyanato equivalent-condition under react for some time; And make formula (IIa) compound and formula (IIIa) compound
Under the condition that is fit to the formula that forms (I) compound, react for some time.
In certain embodiments, reactant has formula (II) and formula (III).
In certain embodiments, in response diagram Ic, urea forming process of the present invention is illustrated, to obtain formula (Ia) compound.Therefore, in certain embodiments, formula (Ia) compound
-wherein the forming member by defined herein-can be prepared by following: make formula (IIc) compound
With formula (III) compound
-wherein Z be isocyanato (NCO) or the isocyanato equivalent-under the condition that is fit to the formula that forms (Ia) compound, react for some time; Or
Make formula (IIc) compound and the reagent that produces isocyanato be fit to the formula that forms (IId) compound
-wherein Y be isocyanato or isocyanato equivalent-condition under react for some time; And make formula (IIa) compound and formula (IIIa) compound
Under the condition that is fit to the formula that forms (Ia) compound, react for some time.
In certain embodiments, reactant has formula (IIc) and formula (III).
In certain embodiments, with respect to the excessive reactant (for example formula (IIa) or (III) compound) that has isocyanato or isocyanato equivalence group that provides of the amount of aniline (for example formula (II) or (IIIa) compound).For example, the mol ratio of formula (II) compound and formula (III) compound, or the mol ratio of formula (IIIa) compound and formula (IIa) compound can be about 1: 1 to about 1: 1.5 or about 1: 1 to about 1: 1.2.In other embodiments, the compound with isocyanato or isocyanato equivalent part can be added in the solution that comprises described aniline.For example, described interpolation can be implemented by a part mode.
In certain embodiments, with respect to the excessive reactant (for example formula (IId) or (III) compound) that has isocyanato or isocyanato equivalence group that provides of the amount of aniline (for example formula (IIc) or (IIIa) compound).For example, the mol ratio of formula (IIc) compound and formula (III) compound, or the mol ratio of formula (IIIa) compound and formula (IId) compound can be about 1: 1 to about 1: 1.5 or about 1: 1 to about 1: 1.2.In other embodiments, the compound with isocyanato or isocyanato equivalent part can be added in the solution that comprises described aniline.For example, described interpolation can be implemented by a part mode.
Described urea forms step and can be according to circumstances exists down and implement at organic solvent (for example aromatic solvent (as benzene, toluene etc.), N, dinethylformamide (DMF), methyl sulfoxide, acetonitrile, ethyl acetate, methylene dichloride, its mixture and like that).In certain embodiments, described reaction solvent comprises toluene.
Described urea forms reaction and can implement under any temperature.For example, the temperature of Shi Heing can be about 0 to about 60 ℃ or about 10 to about 45 ℃.In certain embodiments, described being reflected at allly 10 implemented down to about 20 ℃ low temperature according to appointment.In certain embodiments, urea formation is to implement under inert atmosphere.
In certain embodiments, can before described reaction, aniline parent material (for example formula (II) or (IIIa) compound) be dissolved in the aromatic solvent, form a solution.Aromatic solvent is refluxed for some time can removing at least in part.It is believed that, remove water and can reduce the unwanted by product of formation and increase productive rate.In certain embodiments, be present in after the backflow in the described solution water by volume less than about 5%, less than about 3%, less than about 1%, less than about 0.1%, less than about 0.03% or less than about 0.01%.
In certain embodiments, can before described reaction, aniline parent material (for example formula (IIc) or (IIIa) compound) be dissolved in the aromatic solvent, form a solution.Aromatic solvent is refluxed for some time can removing at least in part.It is believed that, remove water and can reduce the unwanted by product of formation and increase productive rate.In certain embodiments, be present in after the backflow in the described solution water by volume less than about 5%, less than about 3%, less than about 1%, less than about 0.1%, less than about 0.03% or less than about 0.01%.
In certain embodiments, formula (I) compound prepares by making the reaction of formula (II) compound and formula (III) compound.In alternate embodiment, formula (I) compound prepares by making the reaction of formula (IIa) compound and formula (IIIa) compound.
In certain embodiments, formula (Ia) compound through type (IIc) compound and formula (III) compound react and prepare.In alternate embodiment, formula (Ia) compound prepares by making the reaction of formula (IId) compound and formula (IIIa) compound.
The parent material that has an isocyanato and isocyanato equivalent part is for institute's well known in the industry and can buy.These materials can also prepare by the reagent react with the generation isocyanato from corresponding aniline by usual manner, and described reagent comprises the material that can form isocyanato equivalence group with the amino reaction of aniline.For example, have isocyanato compound can (for example phosgene (be Cl with the reagent that produces isocyanato by making corresponding aniline
2C=O) or triphosgene [be carbonic acid two-the trichloromethyl ester, Cl
3COC (O) OCCl
3]) reaction easily is prepared to produce isocyanato derivative (can implement to separate to it according to circumstances subsequently).The processing procedure of another preparation isonitrile acid group comprises to use the reagent thricarbonate two-tertiary butyl ester that produces isocyanato to produce the isonitrile acidic group from aniline as above-mentioned similar fashion.This processing procedure one example is reported in Tetrahedron Lett.1999 by people such as Peerlings, 40, among the 1021-1024, its disclosure all is incorporated herein by reference. and these processing procedures and known in the industry other processing procedure can be as institute's explaination generation isocyanatos among following response diagram IIa, IIb and the IIc.
The isocyanato equivalent comprises a part except that isocyanato, and described part can be by forming a urea key with aniline (for example formula (II), (IIc) and (IIIa) compound) reaction.The isocyanato equivalent can be from the reagent-1 of corresponding aniline by the generation isocyanato) carbonyl dimidazoles and 2) be present in methyl iodide in THF and the acetonitrile-act on successively respectively and prepare, as (for example) by people such as Batey in Tetrahedron Lett.1998,39, set forth among the 6267-6270, its disclosure all is incorporated herein by reference.This processing procedure can generate the isocyanato equivalent as being explained among response diagram IIIa, IIIb and the IIIc hereinafter.
Other isocyanato equivalent can be by making corresponding aniline and the reagent that the produces isocyanato (alkyl chloroformate that is substituted of following formula for example
-R wherein
ABe C
1-8Alkyl and R
BBeing leavings group) reaction for some time produces under the condition of described isocyanato equivalent be fit to forming.In certain embodiments, R
ABe methyl.In other embodiments, R
BBe Cl, Br, I, methanesulfonate, tosylate or like that.In a further embodiment, R
BBe Cl, Br or I; And R in a further embodiment,
BBe Cl.
Among response diagram IVa, IVb and the IVc use being substituted alkyl chloroformate below generates the isocyanato equivalent and sets forth.
Response diagram IVa
Response diagram IVb
Response diagram IVc
Aniline (for example formula (II), (IIc) and (IIIa) compound) (for example) according to the reagent of response diagram IVa, IVb and IVc and generation isocyanato-be substituted alkyl chloroformate-reaction can enforcement in the presence of organic bases according to circumstances.The organic bases that is fit to comprises (for example): pyridine, dimethylamino pyridine, hexahydropyridine, morpholine, its mixture and like that.In certain embodiments, described organic bases is a pyridine.The alternative in some cases leavings group R of described organic bases
BTo form organic alkali derivant.In certain embodiments, the alternative leavings group R of pyridine
BTo form pyridine derivate.
Aniline (for example formula (II), (IIc) reach (IIIa) compound) can be implemented in a solvent according to circumstances with the reaction that is substituted alkyl chloroformate.The solvent that is fit to comprises (for example): polar solvent, and as N, dinethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, ethyl acetate, tetrahydrofuran (THF), methylene dichloride and like that.
Generally speaking, aniline (for example formula (II), (IIc) or (IIIa) compound) can be about 1: 1 to about 1: 2 with the mol ratio that is substituted alkyl chloroformate.In certain embodiments, described ratio is about 1: 1 to about 1: 1.5.These reactions can implemented under any suitable temperature, for example about 0 to about 60 ℃ or about 10 to about 45 ℃.
People generally understand, although described isocyanato or isocyanato equivalent can be isolating, it also can on-the-spotly generate and be directly used in finishes described ureogenesis reaction.Therefore, in certain embodiments, described isocyanato or isocyanato equivalent generate in the scene and aniline reaction then direct without separation and that be fit to.
Go provide protection
According to a further aspect of the invention, formula (II) compound can prepare by the method that comprises following reaction: make formula (IV) compound
-wherein the forming member in provide herein-with go to protect reagent in the conditioned response for some time that is fit to the formula that forms (II) compound.
In certain embodiments, formula (IIc) compound can prepare by the method that comprises following reaction: make formula (IVa) compound
-wherein the forming member in provide herein-be fit to react for some time under the condition of the formula that forms (IIc) compound with removing to protect reagent.
Known a lot of protective material that goes that is fit to is optionally removed the amido protecting group.For example, the chemistry data of blocking group can be referring to Protective Groups in Organic Synthesis (third edition, editor, the Wiley﹠amp of Green and Wuts; Sons, 1999), the document all is incorporated herein by reference.In certain embodiments, optionally removed described amido protecting group (Pr) by hydrolytic action.In other embodiments, the described protective material that goes is alkali, for example mineral alkali.It is the alkali that comprises oxyhydroxide that one exemplary removes to protect reagent, and for example alkali metal hydroxide comprises sodium hydroxide, lithium hydroxide, potassium hydroxide and like that.In certain embodiments, the described protective material that goes is a sodium hydroxide.
Go provide protection in organic solvent, to implement according to circumstances.In certain embodiments, described organic solvent comprises: alcohol, for example methyl alcohol, ethanol, Virahol, n-propyl alcohol, butanols, its mixture or like that.In certain embodiments, described organic solvent comprises methyl alcohol.
Go provide protection under any suitable temperature, to implement.In certain embodiments, go provide protection to implement with room temperature or the temperature that is higher than room temperature.In certain embodiments, go provide protection to implement down at about 0 to about 100, about 20 to about 100, about 30 to about 100, about 40 to about 100, about 50 to about 100 or about 70 to about 90 ℃.In other embodiments, go provide protection under reflux temperature, to implement.
In certain embodiments, describedly go to protect reagent to provide with respect to the amount of formula (IV) compound molar excess.Described therein to remove to protect reagent be among the embodiment of alkali metal hydroxide, and the mol ratio of alkali metal hydroxide and formula (IV) compound is about 1: 1 to about 1: 100, about 1: 1 to about 1: 10, about 1: 3 to about 1: 8 or about 1: 4 to about 1: 6.
In certain embodiments, describedly go to protect reagent to provide with respect to the amount of formula (IVa) compound molar excess.Described therein to remove to protect reagent be among the embodiment of alkali metal hydroxide, and the mol ratio of alkali metal hydroxide and formula (IVa) compound is about 1: 1 to about 1: 100, about 1: 1 to about 1: 10, about 1: 3 to about 1: 8 or about 1: 4 to about 1: 6.
The provide protection of going of formula (IV) compound can be implemented in the presence of the formula V compound according to circumstances:
It can be because of many reasons be present in many batches of formulas (IV) compound, these reasons comprise (for example) handle, separate or other operating period the formula V compound incomplete halogenation or the dehalogenation of formula (IV) compound.
Formula (IV) parent material composition can comprise the formula V compound with arbitrary mole of % according to circumstances, for example less than about 10, less than about 8, less than about 5, less than about 4, less than about 3, less than about 2 or less than about 1 mole of %.The provide protection of going of formula V compound can cause formation (promptly to lack R without halogenated accordingly
3) formula (IIb) unhindered amina:
Therefore, the product of protective reaction may comprise some formulas (IIb) compound.In certain embodiments, the product of protective reaction comprise less than about 10, less than about 8, less than about 5, less than about 4, less than about 3, less than about 2 or less than formula (IIb) compound of about 1 mole of %.
In certain embodiments, the provide protection of going of formula (IVa) compound can be implemented in the presence of formula (Vb) compound according to circumstances:
It can be because of many reasons be present in many batches of formulas (IVa) compound, and these reasons comprise that (for example) is in processing, separation or the incomplete halogenation of other operating period formula (Vb) compound or the dehalogenation of formula (IVa) compound.Formula (IVa) parent material composition can comprise formula (Vb) compound with arbitrary mole of % according to circumstances, for example less than about 10, less than about 8, less than about 5, less than about 4, less than about 3, less than about 2 or less than about 1 mole of %.The provide protection of going of formula (Vb) compound can cause formation (promptly to lack R without halogenated accordingly
3) formula (IIe) unhindered amina:
Therefore, the product of protective reaction may comprise some formulas (IIe) compound.In certain embodiments, the product of protective reaction comprise less than about 10, less than about 8, less than about 5, less than about 4, less than about 3, less than about 2 or less than formula (IIe) compound of about 1 mole of %.
Halogenation
In others of the present invention, formula (IV) compound can prepare by the method that comprises following reaction: make the formula V compound
Under the condition that is fit to production (IV) compound, react for some time with halide reagent.
In certain embodiments of the invention, formula (IVa) compound can prepare by the method that comprises following reaction: make formula (Vb) compound
Under the condition that is fit to production (IVa) compound, react for some time with halide reagent.
Can use the known in the industry halide reagent of many kinds.In certain embodiments, described halide reagent is bromination or chlorination reagent.Some exemplary bromide reagent comprises (for example): Br
2, N-bromosuccinimide (NBS), 1,3-two bromo-5,5-T10, pyridinium tribromideization (pyrHBr
3) and like that.One exemplary chlorination reagent is a N-chlorosuccinimide.In certain embodiments, described halide reagent is a N-bromosuccinimide.
Can use any suitable organic solvent to implement described halogenating reaction according to circumstances.In certain embodiments, described organic solvent comprises: alcohol, for example methyl alcohol, ethanol, n-propyl alcohol, Virahol, butanols, its mixture and like that.In certain embodiments, described organic solvent is a methyl alcohol.In other embodiments, described organic solvent comprises dimethyl formamide or tetrahydrofuran (THF).
The optimal temperature of described halogenating reaction can change.For example, temperature of reaction can be about room temperature or is lower than about room temperature, for example from about 0 to about 25 ℃.
The mol ratio of halide reagent and formula V compound can by the masterful technique workman select in a usual manner or optimization so that the dihalo by product is minimum and make the productive rate maximum of single halogenated product.In certain embodiments, described mol ratio is about 1: 0.8 to about 1: 1: 2, about certainly 1: 0.9 to about 1: 1.1, about certainly 1: 0.95 to about 1: 1.05 or about 1: 1.
The mol ratio of halide reagent and formula (Vb) compound can by the masterful technique workman select in a usual manner or optimization so that the dihalo by product is minimum and make the productive rate maximum of single halogenated product.In certain embodiments, described mol ratio is about 1: 0.8 to about 1: 1: 2, about certainly 1: 0.9 to about 1: 1.1, about certainly 1: 0.95 to about 1: 1.05 or about 1: 1.
Cyclic action
In further aspect of the present invention, the formula V compound can prepare by the method that comprises following reaction: make formula (VI) compound
With one have formula NH
2NH-R
2Alkyl hydrazine under the condition that be fit to form the formula V compound, react for some time.
In certain embodiments, formula (Vb) compound can prepare by the method that comprises following reaction: make formula (VIa) compound
With one have formula NH
2NH-R
2Alkyl hydrazine under the condition that is fit to the formula that forms (Vb) compound, react for some time.
In certain embodiments, described alkyl hydrazine is methylhydrazine (NH
2NH-Me).
Described cyclization can be implemented in the presence of organic solvent according to circumstances.In certain embodiments, described solvent comprises: alcohol, for example methyl alcohol, ethanol, Virahol, n-propyl alcohol, butanols, its mixture and like that.In certain embodiments, described organic solvent comprises methyl alcohol.In certain embodiments, described organic solvent comprises ethanol.In other embodiments, can be with excessive alkyl hydrazine as solvent.
Described cyclization can further be implemented in the presence of acid.In certain embodiments, described acid is mineral acid, for example hydrochloric acid, Hydrogen bromide; Perhaps described acid is organic acid, for example acetate or trifluoroacetic acid.In certain embodiments, described acid is hydrochloric acid.Described alkyl hydrazine is about 1: 0.1 to about 1: 100 with the mol ratio of acid; From about 1: 0.1 to about 1: 20, about certainly 1: 0.5 to about 1: 12, about certainly 1: 1 to about 1: 8 or about certainly 1: 2 to about 1: 6.In certain embodiments, described alkyl hydrazine is about 1: 3 with the mol ratio of acid.In other embodiments, described alkyl hydrazine is greater than about 1: 2 with the mol ratio of acid.
The mol ratio of described formula (VI) compound and alkyl hydrazine can change.In certain embodiments, can the molar excess amount provide alkyl hydrazine.The mol ratio that exemplary is fit to comprises about 1: 1 to about 1: 10, about 1: 1 to about 1: 5, about 1: 1 to about 1: 3, about 1: 1 to about 1: 1.5 or about 1: 1 to about 1: 1.2.
The mol ratio of described formula (VIa) compound and alkyl hydrazine can change.In certain embodiments, can the molar excess amount provide alkyl hydrazine.The mol ratio that exemplary is fit to comprises about 1: 1 to about 1: 10, about 1: 1 to about 1: 5, about 1: 1 to about 1: 3, about 1: 1 to about 1: 1.5 or about 1: 1 to about 1: 1.2.
Described cyclization can be implemented under any temperature.In certain embodiments, described temperature of reaction is room temperature or is lower than room temperature.In a further embodiment, described temperature of reaction is from-10 to about 30 ℃ approximately.In a further embodiment, at first described temperature of reaction is maintained at about-10 to about 0 ℃, more described temperature is kept for some time down at about 5 to about 15 ℃ subsequently, and then described temperature is remained in about 20 to about 25 ℃.
In certain embodiments, described cyclization can comprise in the solution of described alkyl hydrazine and (according to circumstances) a kind of acid (for example HCl) and implements by formula (VI) compound being added into one.
In certain embodiments, described cyclization can comprise in the solution of described alkyl hydrazine and (according to circumstances) a kind of acid (for example HCl) and implements by formula (VIa) compound being added into one.
Described and reaction alkyl hydrazine can further generate byproduct formula (Va) compound according to circumstances:
In certain embodiments, formula (Va) compound generates than formula V compound amount still less with one.For example, the described cyclization mol ratio that can produce a formula V compound and formula (Va) compound greater than about 2, greater than about 4 or greater than about 5 product.
In certain embodiments, the described byproduct compounds of further product according to circumstances is formula (Vc) compound:
In certain embodiments, formula (Vc) compound generates than formula (Vb) compound amount still less with one.For example, the described cyclization mol ratio that can produce the same form (Vb) compound and formula (Vc) compound greater than about 2, greater than about 4 or greater than about 5 product.
Condensation
In another aspect of the invention, the same form (VI) compound is by comprising the method preparation of following reaction: make (VII) compound
Acetal with formula (VIII)
-wherein R and R ' are independent separately is C
1-6Alkyl, aralkyl or alkylaryl, or R and R ' form a 5-or 6-unit Heterocyclylalkyl-react for some time under the condition that is fit to production (VI) compound together with the CH base of O atom that they connected and insertion.
In certain embodiments, formula (VIa) compound is by comprising the method preparation of following reaction: make (VIIa) compound
With the same form (VIII) aldolization, set forth as this paper.
Formula (VIII) acetal can be any of the multiple compound that comprises following substances: (for example) N, the dinethylformamide dimethylacetal, N, the dinethylformamide diethyl acetal, N, dinethylformamide dipropyl acetal, N, dinethylformamide di-isopropyl acetal, N, dinethylformamide dibutyl acetal, N, dinethylformamide two-tertiary butyl acetal and N, dinethylformamide di neo-pentyl acetal, N, dinethylformamide dicyclohexyl acetal, N, dinethylformamide phenylbenzene acetal, N, dinethylformamide Glycol Acetal and N, N, 5,5-tetramethyl--1,3-dioxane-2-amine.In certain embodiments, described acetal is N, the dinethylformamide dimethylacetal.
Described condensation reaction can be implemented in a solvent (for example organic solvent) according to circumstances.In certain embodiments, described solvent comprises: alcohol, for example methyl alcohol, ethanol, n-propyl alcohol, Virahol, butanols, amylalcohol, its mixture and like that.In certain embodiments, described solvent is an ethanol.In other embodiments, described solvent is a methyl alcohol.In other embodiment, can be with excessive acetal as solvent.
In certain embodiments, described condensation reaction is implemented in the solvent identical with described cyclization.In other embodiments, the product of described condensation reaction before implementing described cyclization without separation.
Described condensation reaction can be implemented down in any optimal temperature (for example room temperature or be higher than room temperature).In certain embodiments, described temperature of reaction is from about 20 to about 95 ℃, about 20 to about 85 ℃ or about 20 to about 75 ℃.In other embodiments, described temperature of reaction is a reflux temperature.
Described condensation reaction can be according to circumstances by implementing in the mixture that formula (VIII) acetal is added into the same form (VII) compound and solvent.Described mixture can be homogeneous or heterogeneous.
In certain embodiments, described acetal can with respect to formula (VII) compound for amount excessive the mole provide.Described acetal and formula (VII) examples for compounds mol ratio comprises about 1.1 to about 10, about 1.2 to about 5 or about 1.5 to about 3.
The processing procedure intermediate
The present invention further provides formula (II), (IV), (V) and processing procedure intermediate (VI):
-wherein the forming member is provided by this paper.
In certain embodiments, R
5There are two to be H in the group.
Certain embodiments of the invention provide formula (IIc), (IVa), (Vb) and processing procedure intermediate (VIa):
In certain embodiments, R
5When occurring H at every turn.
Definition
Should be appreciated that, for the purpose of clear, also can in single embodiment, provide with array mode in conjunction with independent described some feature of the present invention of embodiment.On the contrary, for also providing separately or in any suitable sub-portfolio mode in conjunction with the described various features of single embodiment for simplicity.
As used herein, term " alkyl " desire refers to saturated hydrocarbyl straight chain or the tool side chain.The exemplary alkyl comprises methyl (Me), ethyl (Et), propyl group (for example n-propyl and sec.-propyl), butyl (for example N normal-butyl, isobutyl-, the tertiary butyl), amyl group (for example n-pentyl, isopentyl, neo-pentyl) and like that.Alkyl can comprise 1 to about 20, from 2 to about 20, from 1 to about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4 or from 1 to about 3 carbon atoms.
As used herein, " thiazolinyl " refers to have the alkyl of one or more pair C-C.The exemplary thiazolinyl comprises vinyl, propenyl, cyclohexenyl and like that.
As used herein, " alkynyl " refers to have the alkyl of one or more three C-C.The exemplary alkynyl comprises ethynyl, proyl and like that.
As used herein, " haloalkyl " refers to have the alkyl of one or more halogenic substituent.The exemplary haloalkyl comprises CF
3, C
2F
5, CHF
2, CCl
3, CHCl
2, C
2Cl
5And it is like that.Wherein all hydrogen atom all be can be described as " whole haloalkyl " by the alkyl that halogen atom replaces.
As used herein, " carbocylic radical " refers to as saturated (promptly not comprising two keys or triple bond) or the group of undersaturated (promptly comprising one or more pair key or triple bond) cyclic hydrocarbon part.Carbocylic radical can be monocyclic or polycyclic.The Exemplary carbon cyclic group comprises that cyclopropyl, cyclobutyl, ring defend base, cyclohexyl, suberyl, cyclopentenyl, 1 base, cyclohexenyl, norcamphanyl, fall pinane base, norcaryl, adamantyl, phenyl and like that.Carbocylic radical can be (for example " cycloalkyl ") of aromatics family (for example " aryl ") or non-aromatics family.In certain embodiments, carbocylic radical can have from 3 to about 20,3 to about 10 or 3 to about 7 carbon atoms.
As used herein, " aryl " refers to monocyclic or polycyclic aromatic hydrocarbons, for example phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl and like that.In certain embodiments, aryl has from 6 to about 20 carbon atoms.
" cycloalkyl " as used herein refers to non-aromatics family hydro carbons, comprises alkyl, thiazolinyl and the alkynyl of cyclisation.Cycloalkyl can comprise monocycle, two ring or polycyclic loop systems and two key and triple bonds.The exemplary cycloalkyl comprises that cyclopropyl, cyclobutyl, ring defend base, cyclohexyl, suberyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatriene base, norcamphanyl, fall pinane base, norcaryl, adamantyl and like that.Also contain in the cycloalkyl definition and have one or more and condense (that is a key shared) part to the aromatics family ring of cycloalkyl ring (for example benzo derivative of pentane, hexane and like that) with it.
As used herein, " heterocyclic radical " refers to can be the group of saturated or unsaturated carbocylic radical, and one or more of wherein said carbocylic radical becomes ring carbon atom to be replaced by heteroatoms (for example O, S or N).Heterocyclic radical can be (for example " Heterocyclylalkyl ") of aromatics family (for example " heteroaryl ") or non-aromatics family.Heterocyclic radical can be corresponding to hydrogenant and partially hydrogenated heteroaryl.Assorted carbocylic radical can comprise (except that at least one heteroatoms) about certainly 1 to about 20, about 2 to about 10 or about 2 to about 7 carbon atoms and can connect via a carbon atom or heteroatoms.In certain embodiments, heterocyclic radical can have from 3 to 20,3 to 10,3 to 7 or 5 to 7 one-tenth annular atomses.In addition, heterocyclic radical can be substituted or be unsubstituted.The heterocyclic radical example comprises that morpholino, thiomorpholine are for base, piperazinyl, tetrahydrofuran base, tetrahydro-thienyl, 2,3-dihydro benzo furyl, 1,3-benzodioxole, phendioxin, 4-dioxane, piperidyl, pyrrolidyl, isoxazole alkyl, different thiazolidine base, pyrazoles pyridine Ji, oxazolidinyl, thiazolidine base, imidazolidyl and like that and arbitrary group that lists at heteroaryl and Heterocyclylalkyl.
As used herein, " heteroaryl " is for having at least one heteroatomic ring member's (for example sulphur, oxygen or nitrogen) monocycle and polycyclic aromatic family hydro carbons.Heteroaryl includes, but is not limited to: pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indyl, pyrryl oxazolyl, benzofuryl, benzothienyl, benzothiazolyl isoxazolyl, pyrazolyl, triazolyl, tetrazyl, indazolyl, 1,2, the 4-thiadiazolyl group, isothiazolyl, benzothienyl, purine radicals, carbazyl, benzimidazolyl-, 2, the 3-dihydro benzo furyl, 2,3-dihydroxy benzothienyl, 2,3-dihydroxy benzothienyl-S-oxide compound, 2,3-dihydroxy benzothienyl-S-dioxide; benzoxazole quinoline-2-ketone-Ji, the indoline base, the benzo dioxolanyl, benzodioxan and like that.In certain embodiments, heteroaryl can have from 1 to about 20 carbon atoms, and has in other embodiments from about 3 to about 20 carbon atoms.In certain embodiments, heteroaryl has 1 to about 4,1 to about 3 or 1 to 2 heteroatoms.
As used herein, " Heterocyclylalkyl " refers to wherein one or more cycloalkyl that becomes ring carbon atom to be replaced by heteroatoms (for example O, S, N or P atom).The definition of Heterocyclylalkyl is also contained and is had one or more and condense (that is a key shared with it) part to the aromatics family of non-aromatics family's heterocycle (for example benzo derivative of phthalimide-based, adjacent naphthalimido, pyromellitic acid imide base, phthalic diamide phenyl and saturated heterocyclic (for example indomethacin base and isoindole Mei Xinji)) ring.
As used herein, " halo (halo) " or " halogen (halogen) " comprises fluoro, chloro, bromo and iodo.
As used herein, " alkoxyl group " refers to one-O-alkyl.The exemplary alkoxyl group comprises methoxyl group, oxyethyl group, propoxy-(for example, positive propoxy and isopropoxy), tert.-butoxy and like that.
As used herein, " halogenated alkoxy " refers to the alkoxyl group through at least one halogeno-group replacement.
As used herein, " thio alkoxy " refers to that wherein the O atom is by the alkoxyl group of S atom replacement.
As used herein, " halo thio alkoxy " refers to the thio alkoxy through at least one halogeno-group replacement.
As used herein, " acyl group " refers to the carbonyl by H, alkyl, thiazolinyl, alkynyl or carbocylic radical replacement.The exemplary acyl group comprises formyl radical or ethanoyl.
As used herein, " acyloxy " refers to-the O-acyl group.
As used herein, " carboxylic acid amides " or " aminocarboxyl " refers to-C (O) NH
2
As used herein, " alkyl carboxylic acid amides " or " alkyl amino-carbonyl " refer to-C (O) NH (alkyl).
As used herein, " dialkyl group carboxylic acid amides " or " dialkylamino carbonyl " refers to-C (O) N (alkyl)
2
As used herein, " sulphonamide " refers to-S (O) NH
2
As used herein, " alkyl sulfonamide " refers to-S (O) NH (alkyl).
As used herein, " dialkyl group sulphonamide " refers to-S (O) N (alkyl)
2
As used herein, " alkylsulfonyl " refers to SO
2
As used herein, " sulfinyl " refers to SO.
As used herein, " alkyl sulphinyl " refers to the sulfinyl through the alkyl replacement.
As used herein, " haloalkyl sulfinyl " refers to the sulfinyl through the haloalkyl replacement.
As used herein, " aryl sulfonyl kia " refers to the sulfinyl through the aryl replacement.
As used herein, " alkyl sulphonyl " refers to the alkylsulfonyl through the alkyl replacement.
As used herein, " halogenated alkyl sulfonyl " refers to the alkylsulfonyl through the haloalkyl replacement.
As used herein, " aryl sulfonyl " refers to the alkylsulfonyl through the aryl replacement.
As used herein, " urea groups " refers to-NHC (O) NH
2
As used herein, " alkyl urea groups " refers to the urea groups through the alkyl replacement.
As used herein, " amino " refers to NH
2
As used herein, " alkylamino " refers to the amino through the alkyl replacement.
As used herein, " dialkylamino " refers to the amino through two alkyl replacements.
As used herein, " carbalkoxy " refers to-CO-(alkoxyl group).
As used herein, " haloalkoxy carbonyl " refers to-CO-(halogenated alkoxy).
As used herein, " carbocylic radical alkyl " refers to the alkyl through the carbocylic radical replacement.
As used herein, " aralkyl " refers to the moieties through the aryl replacement.The exemplary aralkyl comprises: benzyl, styroyl and menaphthyl.In certain embodiments, aralkyl has from 7 to 20 or 7 to 11 carbon atoms.
As used herein, " heterocyclic radical alkyl " refers to the alkyl through the heterocyclic radical replacement.
As used herein, " Heterocyclylalkyl alkyl " refers to the alkyl through the Heterocyclylalkyl replacement.
As used herein, term " reaction " uses and is often referred to by known case in the industry puts chemical reagent together so that make it interact and reach the chemistry or the physical conversion of at least a chemical reagent at molecular level in this mode.
As used herein, term " is substituted " and refers in molecule or group with non-hydrogen partial substituting hydrogen partial.
As used herein, term " leavings group " refers to during chemical reaction the part that can replace by nucleophillic attack through another part (for example).Leavings group is by being known in the industry and being comprised (for example): halogen, hydroxyl, alkoxyl group ,-O (CO) R
a,-OSO
2-R
bAnd-Si (R
c)
3, R wherein
aCan be C
1-C
8Alkyl, C
3-C
7Cycloalkyl, aryl, heteroaryl or Heterocyclylalkyl, wherein R
bCan be C
1-C
8Alkyl, aryl are (according to circumstances through one or more halogen, cyano group, nitro, C
1-C
4Alkyl, C
1-C
4Haloalkyl, C
1-C
4Alkoxyl group or C
1-C
4Halogenated alkoxy replaces) or heteroaryl (according to circumstances through one or more halogen, cyano group, nitro, C
1-C
4Alkyl, C
1-C
4Haloalkyl, C
1-C
4Alkoxyl group or C
1-C
4Halogenated alkoxy replaces), and R wherein
cCan be C
1-C
8Alkyl.The exemplary leavings group comprises: chloro, bromo, iodo, methanesulfonate, tosylate, TMS and like that.
Term used herein " amido protecting group " refers to non-hydrogen amino substituting group, the amido functional group that is easy to react with the reversible manner protection when it can other functional group on compound reacts." ring amido protecting group " refers to that one can comprise the amido protecting group of protected amino part in the ring, phthalimido for example, or like that.Amido protecting group example comprises formyl radical, ethanoyl, trityl, the tribromo-acetyl base, chloracetyl, acetyl bromide, iodo ethanoyl and urethanes blocking group, carbobenzoxy-(Cbz) for example, 4-phenyl-carbobenzoxy-(Cbz), 2-methyl benzyloxycarbonyl, 4-methoxyl group-carbobenzoxy-(Cbz), 4-fluoro-carbobenzoxy-(Cbz), 4-chloro-carbobenzoxy-(Cbz), 3-chloro-carbobenzoxy-(Cbz), 2-chloro-carbobenzoxy-(Cbz), 2,4-dichloro--carbobenzoxy-(Cbz), 4-bromo-carbobenzoxy-(Cbz), 3-bromo-carbobenzoxy-(Cbz), 4-nitro-carbobenzoxy-(Cbz), 4-cyano group-carbobenzoxy-(Cbz), tertbutyloxycarbonyl, 2-(4-xenyl)-isopropoxy carbonyl, 1,1-phenylbenzene second-1-base oxygen carbonyl, 1,1-diphenylprop-1-base oxygen carbonyl, 2-phenyl third-2-base oxygen carbonyl, 2-(right-tolyl)-third-2-base oxygen carbonyl, cyclopentenyl oxygen base carbonyl, 1-methyl-cyclopentenyl oxygen base carbonyl, cyclohexyl oxygen base carbonyl, 1-methylcyclohexyl oxygen base carbonyl, 2-methylcyclohexyl oxygen base carbonyl, 2-(4-toluyl alkylsulfonyl)-ethoxycarbonyl, 2-(methyl sulphonyl) ethoxycarbonyl, 2-(triphenylphosphinyl)-ethoxycarbonyl, Fluorene base methoxycarbonyl (FMOC), 2-(TMS) ethoxycarbonyl, allyloxy carbonyl, 1-(trimethyl silyl methyl) third-1-thiazolinyl oxygen base carbonyl, 5-benzisoxa oxalyl group methoxyl group-carbonyl, 4-acetoxyl group benzyloxycarbonyl, 2,2, the 2-trichloro-ethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl, the cyclopropyl methoxycarbonyl, 4-(oxygen base in the last of the ten Heavenly stems) carbobenzoxy-(Cbz), isobornyl oxygen base-carbonyl, piperidino oxygen base carbonyl and like that; Benzyl acyl group methyl sulphonyl, 2-oil of mirbane sulfinyl, diphenylphosphine oxide compound and similar amido protecting group.The kind of amido protecting group that adopts unimportant, as long as described be stable through the amino condition of deriving to the reaction on other position of intermediate molecule, carried out subsequently, and can optionally remove and can not destroy the rest part of described molecule at appropriate location.In certain embodiments, described amido protecting group is tertbutyloxycarbonyl (t-Boc), allyloxy carbonyl and carbobenzoxy-(Cbz) (CbZ).In other embodiments, described amido protecting group is an acyl group, for example formyl radical or ethanoyl.Other example of amido protecting group is referring to the Protecting Groups in OrganicChemistry (J.G.W.McOmie, editor's 1973, the 2 chapters) of E.Haslam; The Protective Groups in Organic Synthesis (1991, the 7 chapter) of T.W Greene and P.G.M.Wuts; And the Protective Groups in Organic Synthesis (the 3rd edition, 1999, the 7 chapters) of T.W.Greene and P.G.M.Wuts.
Phrase as used herein " amount that can not seek and visit in fact " refers to following compound amount: described compound or do not exist in a composition or exist or being that an amount of comparing with the major ingredient of described composition less than about 0.5 mole of % exists through seeking and visiting with the amount that can not seek and visit by the routine analysis mode.
Processing procedure described herein can be monitored according to any known in the industry method.For example, product constitute can pass through spectrography (for example NMR spectroscopy (as
1H or
13C), infrared spectroscopy, spectrophotometry (as the UV-visible light) or mass spectrometry) or by chromatography (for example high performance liquid chromatography (HPLC) or thin layer chromatography) monitoring.
In certain embodiments, the preparation of compound can relate to the protection of all cpds group and go provide protection.Protection and remove the needs of provide protection and the selection of due care group can easily be determined by those of skill in the art in the industry.For example, the chemistry data of blocking group can be referring to people's such as Greene and Wuts Protective Groups inOrganic Synthesis (third edition, editor, Wiley ﹠amp; Sons, 1999), described document all is incorporated herein by reference.
The reaction of processing procedure described herein can be implemented in can be by the organic synthesis suitable solvent that those of skill in the art easily select in the industry.Implementing under the temperature of described reaction (for example from the freezing temperature of the described solvent temperature to the scope of the boiling temperature of described solvent), suitable solvent can be nonreactive in fact with parent material (reactant), intermediate or product.Given reaction can be implemented in a kind of solvent or the mixture more than a kind of solvent.Look closely specific reactions steps, can select the suitable solvent of a specific reactions steps.In certain embodiments, reaction can be implemented under the situation that does not have solvent, for example when at least one reagent is liquid or gas.
The solvent that is fit to can comprise halogenated solvent, tetracol phenixin for example, bromodichloromethane, two bromochloromethanes, bromofom, chloroform, bromochloromethane, methylene bromide, Butyryl Chloride, methylene dichloride, zellon, trieline, 1,1, the 1-trichloroethane, 1,1, the 2-trichloroethane, 1, the 1-ethylene dichloride, 2 cbloropropane isopropyl chloride, phenyl-hexafluoride, 1,2, the 4-trichlorobenzene, orthodichlorobenzene, chlorobenzene, fluorobenzene, fluoro trichloromethane, chlorotrifluoromethane, bromotrifluoro-methane, tetrafluoro-methane, dichlorofluoromethane, chlorodifluoromethane, trifluoromethane, 1,2-dichloro tetrafluoro ethane and hexafluoroethane.
The ether solvents that is fit to comprises: Methylal(dimethoxymethane), tetrahydrofuran (THF), 1,3-dioxane, 1,4-dioxane, furans, diethyl ether, glycol dimethyl ether, ethylene glycol diethyl ether, Diethylene Glycol diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethylformamide dimethyl ether, phenylmethylether or t-butyl methyl ether.
The protonic solvent that is fit to can comprise (such as but not limited to): water, methyl alcohol, ethanol, 2-nitroethyl alcohol, 2-fluoroethanol, 2,2,2-TFE, ethylene glycol, 1-propyl alcohol, 2-propyl alcohol, 2-methoxyethanol, 1-butanols, 2-butanols, isopropylcarbinol, the trimethyl carbinol, cellosolvo, Diethylene Glycol, 1-, 2-or 3-amylalcohol, neopentyl alcohol, tertiary amyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, hexalin, benzylalcohol, phenol or glycerine.
The aprotic solvent that is fit to can comprise (such as but not limited to): tetrahydrofuran (THF) (THF), dimethyl formamide (DMF), N,N-DIMETHYLACETAMIDE (DMAC), 1,3-dimethyl-3,4,5,6-tetrahydrochysene-2 (1H)-pyrimidone (DMPU), 1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrole alkyl (NMP), methane amide, the N-methylacetamide, the N-methylformamide, acetonitrile, dimethyl sulfoxide (DMSO), propionitrile, ethyl formate, methyl acetate, hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, tetramethylene sulfone, N, N-dimethyl propylene acid amides, tetramethyl-urea, Nitromethane 99Min., oil of mirbane or hexamethyl-phosphoramide.
The hydrocarbon solvent that is fit to comprises: benzene, hexanaphthene, pentane, hexane, toluene, suberane, methylcyclohexane, heptane, ethylbenzene ,-, adjacent-or right-dimethylbenzene, octane, indane, nonane or naphthalene.
Also can be with supercritical co as solvent.
The reaction of processing procedure described herein can be implemented under the proper temperature that can easily be determined by the masterful technique workman.Temperature of reaction should depend on the fusing point and the boiling point of (for example) described reagent and solvent (if existence); The thermodynamics of described reaction (for example, the reaction of very exothermic may need to implement at low temperatures); And the kinetics of described reaction (for example, one highly activate energy barrier may need high temperature).Temperature (about 25 ℃) and " low temperature " that " high temperature " refers to be higher than room temperature refer to subambient temperature.
The reaction of processing procedure described herein can be implemented in air or under inert atmosphere.Usually, comprise in fact can using to the known synthetic technology of skilled manpower and implement air-sensitive with the reaction of the reagent of air reaction or product.
In certain embodiments, the preparation of compound can comprise that interpolation acid or alkali are with the catalysis of realization (for example) desired reaction or the formation of salt form (for example acid salt).
Exemplary acid can be mineral acid or organic acid.Mineral acid comprises: hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid and nitric acid.Organic acid comprises: formic acid, acetate, propionic acid, butyric acid, methylsulfonic acid, tosic acid, Phenylsulfonic acid, trifluoroacetic acid, propynoic acid, butyric acid, tetrolic acid, vinylacetic acid, valeric acid, caproic acid, enanthic acid, sad, n-nonanoic acid and capric acid.
Exemplary alkali comprises: lithium hydroxide, sodium hydroxide, potassium hydroxide, Quilonum Retard, yellow soda ash and salt of wormwood.Some exemplary highly basic includes, but is not limited to: oxyhydroxide, alcoholate, metal amide class, metal hydride, metal dialkyl amides and arylamines, and wherein: alcoholate comprises lithium, sodium and the sylvite of methyl, ethyl and tertiary butyl oxide compound; The metal amide class comprises: sodium amide, potassium amide and Lithamide; Metal hydride comprises: sodium hydride, potassium hydride KH and lithium hydride: and the metal dialkyl amides comprises the sodium and the sylvite of the amides that replaces through methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, TMS and cyclohexyl.
Compound described herein can be asymmetric (for example having one or more stereocenter).Except as otherwise noted, should contain all steric isomers (for example optically active enantiomorph and diastereomer).Comprising can the tool optically active or racemic isolated in form through the The compounds of this invention of the carbon atom of asymmetric replacement.How the method for preparing the optical activity form from the parent material of tool optically active is understood by the insider, for example by the separation of racemic mixture or by the stereoselectivity synthesis method.
Processing procedure described herein can be stereoselective, so that any product with the same steric isomer enrichment of the chiral reagent of one or more steric isomer enrichment initial given reaction can formation.The enforcement of described reaction should make the product of described reaction can keep one or more in fact to be present in chiral centre in the parent material.The enforcement of described reaction also can make the product of described reaction comprise one with respect to being present in the chiral centre that corresponding chiral centre in the described parent material is counter-rotating in fact.
The separation of the racemic mixture of compound can be implemented by many currently known methodss in the industry.Exemplary methods comprises the fractional recrystallization (separation of for example non-mapping salt) of using " chiral separation acid " (it is the salify organic acid of tool optically active).Be used for of the acid of the suitable separating agent of fractional recrystallization method for (for example) tool optically active; the for example camphorsulfonic acid of D and L type tartrate, diacetyl tartrate, dibenzoyl tartaric acid, Mandelic Acid, oxysuccinic acid, lactic acid or various tool optically actives, for example P-camphorsulfonic acid.Other separating agent that is suitable for the fractional crystallization method comprises: the α-Jia Bianji amine of the pure form of steric isomer (for example S and R type, or the pure form of diastereomer), 2-phenyl glycinol, go first fiber crops sulphur alkali, numb sulphur alkali, N-methylephedrine, cyclohexylethylamine, 1,2-diamino-cyclohexane and like that.
The separation of racemic mixture also can be implemented by carrying out wash-out on the post of filling at the separating agent (for example dinitrobenzene benzyl acyl group phenylglycocoll) of apparatus optically active.The eluting solvent composition that is fit to can be by those of skill in the art are definite in the industry.
The compounds of this invention also can be included in all isotropic substances of the atom that occurs in intermediate or the final compound.Isotropic substance comprises that those have identical ordination number but have the atom of different proton numbers.For example, the isotropic substance of hydrogen comprises tritium and deuterium.
The compounds of this invention also can comprise tautomeric form, for example the keto-enol tautomerism body.Each tautomeric form can balancedly exist or be locked as a kind of three-dimensional form by the metalepsy that is fit to.
The present invention also comprises the salt form of compound described herein.The example of salt (or salt form) includes, but is not limited to: an alkali metal salt or the organic salt and like that of the mineral salt of alkali formula residue (for example amine) or organic acid salt, acid residue (for example carboxylic acid).Generally speaking, described salt form can be by making free alkali or acid and desired salify stoichiometric quantity or excessive is inorganic or organic acid or alkali react and prepares in a suitable solvent or all kinds of SOLVENTS make up.Suitable salt is shown among the Remington ' s Pharmaceutical Sciences (the 17th edition, Mack Publishing Company, Easton, Pa., 1985, the 1418 pages), and its disclosure all is incorporated herein with way of reference.
When implementing the preparation of compound, can use common separation and purification process (for example concentrate, filtration, extraction, Solid-Phase Extraction, recrystallization, chromatography and like that) to separate the product of expectation according to processing procedure described herein.
This paper will more at large set forth the present invention by specific examples.The purpose that following example is provided is not to be to desire to limit the present invention by any way in order to describe.Those in the industry those skilled in the art should easily confirm multiple non-key parameter, can change or revise described parameter to obtain identical result basically.
Example
Example 1: preparation 3-dimethylamino-1-(2 '-methoxyl group-5 '-the acetamido phenyl) third-2-alkene-1-ketone (4).
Under 22 ℃ and nitrogen atmosphere, while stirring dimethylformamide dimethyl acetal (693.3g) is added into 2 '-methoxyl group-5 '-the acetamido methyl phenyl ketone (
3, 1215.1g) be present in the suspension in the ethanol (12.15L).To after gained suspension enforcement stirring and refluxing 18 hours, all solids dissolves all under nitrogen atmosphere, and (346.2g) is added in the homogeneous reaction mixture with other dimethylformamide dimethyl acetal.Under nitrogen atmosphere, continue to implement to stir and refluxed 30 hours again, add other dimethylformamide dimethyl acetal (346.2g) afterwards.Under nitrogen atmosphere, described reaction mixture implemented to stir then and refluxed last 17.5 hours, afterwards＜45 ℃ and＜be a solid residue under the condition of 50mm HgA with described reaction mixture rotary evaporation,＜45 ℃ and＜after further dried overnight, obtain brown solid 4 (1547.9g, 100.6% productive rate) under the condition of 1mm HgA.LC/MS analyzes demonstration, has 98.3% and 100% respectively before solvent evaporation and after the evaporation
3Extremely
4Conversion.
Example 2: preparation 5-(2 '-methoxyl group-5 '-acetylamino phenyl)-1-methyl isophthalic acid H-pyrazoles (5).
With methyl hydrazine (319.3g) be added under the nitrogen through stir and refrigerative methyl alcohol (13.931L) in.(37wt% 1859.6g) uses the reactor jacket cooling to remain on-12 to-7 ℃ with described through stirred solution to allow to add water-based HCl with enough slow speed subsequently.When continuing down when nitrogen stirs at-10 ℃, added through ten minutes solid form 3-dimethylamino-1-(2 '-methoxyl group-5 '-acetylamino phenyl) third-2-alkene-1-ketone (
4, 1546.9g).Under nitrogen, gained homogeneous dark brown solution is at first implemented down to stir and implemented down to stir in 5.5 hours at 10 ℃ subsequently in 3 hours at 0 ℃, add 33% ammoniacal liquor (1090mL) with enough slow speed (25 minutes) then and use the reactor jacket cooling to remain on 8.6 to 15.2 ℃ through stirred solution described to allow.Before ammonia treatment, the LC/MS of described reaction mixture analyzed and show 97.3%
4Extremely
5And its conversion of other N-methylpyrazole isomers (with 83.3: 13.2 ratio), and after ammonia treatment, the LC/MS of described reaction mixture analyzed and show 100%
4Extremely
5And the conversion of its other N-methylpyrazole isomers (with 87.8: 12.2 ratio).The interpolation of ammoniacal liquor makes the pH value of described reaction mixture be increased to 8.Then at normal atmosphere and be increased in the reaction mixture that stirs of hanging oneself under 74.4 ℃ the internal temperature distillation and remove methyl alcohol (about 12L).Also utilize stirring to make this temperature keep finishing in 44 hours the product crystallization that when described distillation finishes, begins by described reaction mixture being cooled to-2 ℃.The LC/MS that the liquid phase of described crystalline mixture is implemented analyzes demonstration,
5And the ratio of another N-methylpyrazole isomers is about 1: 3.(
5More height ratio: other isometry in the described liquid phase is known from experience infringement product yield, and low ratio can damage product purity.In either case, all can be by under atmospheric pressure being back to reflux state and repeating crystallization through the heating that stirs the mixture with described, and before recrystallization, or distillation is removed more methyl alcohol (if ratio height) or is added other methyl alcohol (if ratio is low).) by suction described reaction mixture is implemented to filter, and with 0 ℃ water (3L, then 2 * 500mL) to the solid that leaches implement washing and 40 ℃ and＜condition of 1mm HgA under drying in addition, provide
5(1157.7g, 80.0% productive rate).
Example 3: preparation 5-(2 '-methoxyl group-5 '-acetylamino phenyl)-4-bromo-1-methyl isophthalic acid H-pyrazoles (
6).
To a 5-(2 '-methoxyl group-5 '-acetylamino phenyl)-1-methyl isophthalic acid H-pyrazoles (
5, what 1141.8g) be dissolved in methyl alcohol (13.75L) can remain on described reaction mixture 13.5 to 22.5 ℃ by part adding solid N-bromosuccinimide (911.5g) so that utilize reactor jacket to cool off with enough slow speed in the solution through stirring under nitrogen.About 3/4ths place's bromo pyrazoles 6 in described interpolation process begin precipitation, and this process was finished through about 20 minutes.22 ℃ of following continuously stirring after 30 minutes, the LC/MS of described reacting slurry analyzed show
5Extremely
6Conversion fully; No longer include the parent material that to seek and visit
5Be distilled to essence drying with described through stirred reaction mixture at 10mm HgA and under then up to 30 ℃ internal temperature.With the fragmentation of gained solid residue, and in the solution of a sodium hydroxide (482.25g) water-soluble (11.538L), it is being implemented slurrying 1 hour to remove the succinimide by product under 25 ℃, filtered by suction, (2 * 1000mL) implement washing to water, and under the condition of 22 ℃ and about 10mm HgA, carry out drying, provide
6(1385.7g, 91.8% thick productive rate) (only remarkable impurity that wherein comprises about 3.2 moles of %
5).
Example 4: preparation 5-(2 '-methoxyl group-5 '-aminophenyl)-4-bromo-1-methyl isophthalic acid H-pyrazoles (
7)
Under 22 ℃ and nitrogen in methyl alcohol (13.3L) to the described 5-that obtains from previous examples (2 '-methoxyl group-5 '-acetylamino phenyl)-4-bromo-1-methyl isophthalic acid H-pyrazoles (
6, 1385.7g) (by about 3.2 moles of %'s
5Pollute) enforcement slurrying.In gained suspension under 22 ℃ and nitrogen, divide three parts and add solid N-bromosuccinimides (136.7g altogether) through stirring.First part of N-bromosuccinimide (68.3g) stayed about 2.8 moles of % after 80 minutes unreacted
5It is unreacted that second part of N-bromosuccinimide (34.2g) stayed about 1.8 moles of % after other 60 minutes then
5Then, after adding the 3rd part of N-bromosuccinimide (34.2g),
5Extremely
6Conversion in 15 minutes, finish.No longer include the parent material that to seek and visit
5In stirred suspension, add aqueous sodium hydroxide solution (50wt% with an enough slow speed through 35 fens clockwise 6 subsequently; 2606.8g) so that utilize the reactor jacket cooling that described reaction mixture is remained on 10.4 to 24 ℃.After adding aqueous sodium hydroxide solution, find that a reaction mixture sample comprises about 2.5 moles of %'s
6The debrominate of amount
5Then at 10mm HgA and be increased under 84 ℃ the internal temperature and methyl alcohol (about 12L) distillation in described reaction mixture through stirring removed through 8 hours.LC/MS to described reaction mixture (existing for the dense thick of about 5.5L but the suspension that can stir) shows that 6 to 7 (reach about 2 moles of %'s
7The debrominate analogue) complete hydrolysis.At 10mm HgA and be increased under 55 ℃ the internal temperature and can stay a resistates that can not stir to the removal operation that in fact all remains methyl alcohol (about 1.6 liters) by continuous still battery through four hours.When adding diisopropyl ether (12L) and water (1000mL) and being heated to 65 ℃, described mixture becomes and can stir, and described solid dissolves fully, and two kinds of solid phases are provided.Lower floor's phase (water) is extracted out from upper strata phase (organic phase), use other water (1000mL) that it is implemented extraction subsequently again.Water is merged, and implement extraction with more diisopropyl ether (4L).After water (1000mL) extraction, the second upper strata phase (organic phase) is merged mutually with first upper strata, and the gained mixture is reheated to 50 ℃, to dissolve all solids fully.Utilized stirring to make gained diisopropyl ether solution be cooled to-5 ℃ through 7 hours, 7 crystallization has taken place during this period.Under-5 ℃ again after stirring 5 hours, by suction gained suspension is filtered.With 0 ℃ diisopropyl ether (1.0L) to the solid that leaches implement washing and 40 ℃ and＜it is implemented under the condition of 1mm HgA dryly, obtain
7(979.6g, 81.2% productive rate), recording its purity by HPLC is 99.2%, wherein comprises the main impurity debrominate of about 0.3wt%
7Crystallization and washing lotion are merged, and in a rotary evaporator at first under 69 ℃ and normal atmosphere, under the condition of＜40 ℃ and 10mm HgA, implement evaporation subsequently, a faint yellow solid resistates is provided
7(recording purity by HPLC is 94.3% for 151.49g, 12.6% productive rate, wherein comprises the main impurity debrominate of about 3.5wt%
7).
Example 5:N-(2,4-phenyl-difluoride base)-N '-(4-methoxyl group-3-(4 '-bromo-1 ' methyl isophthalic acid H-pyrazoles-5 '-yl) phenyl) urea (8).
By under 27.6 ℃, be dissolved in two portions 5-that toluene (15L) will obtain from previous example (2 '-methoxyl group-5 '-aminophenyl-4-bromo-1-methyl isophthalic acid H-pyrazoles (7) merges, gained solution is implemented suction filtration, and under the condition of＜50 ℃ and 10mmHgA with the filtrate rotary evaporation to constant weight 1127.0g.The solution that 7 (1102.0g of described 1127.0g residue on evaporation) is dissolved in toluene (11.02L) is implemented to stir, and passes dean stark trap (Dean-Stark trap) and under atmospheric pressure implement to reflux under nitrogen, to remove 0.8mL water.When phlegma become very clarification, in dean stark trap, no longer include water and gather after, under nitrogen, toluene solution is cooled to 12.9 ℃.To under nitrogen gained solution through stir in added isocyanic acid 2,4 difluorobenzene base ester (617.9g) so that utilize reactor jacket cooling described reaction mixture remained on 12.9 to 19 ℃ through 40 minutes by feed hopper with enough slow speed.At half place of described interpolation process, beginning in the described reaction mixture has solid precipitation.After described interpolation has been finished, under 16 ℃ and nitrogen, described reacting slurry is proceeded to stir.After described interpolation has been finished,
7Extremely
8Conversion in the time of 5,60 and 120 minutes, be respectively 90%, 91.2% and 92.6%.When finishing described interpolation after 3 hours, add second section isocyanic acid 2,4 difluorobenzene base ester (24.4g), and under 16 ℃ and nitrogen, continue to stir described reaction mixture again after 30 minutes,
7Extremely
8Be converted into 94%.After adding 1 hour for the second time, add third part isocyanic acid 2,4 difluorobenzene base ester (9.7g), and, under 16 ℃ and nitrogen, continue to stir described reaction mixture again after 15 minutes,
7Extremely
8Be converted into 95%.Under 20 ℃ and nitrogen, stirred described reaction mixture 14.75 hours more then, afterwards 7 to 8 be converted into 100%.Described reaction mixture is implemented suction filtration, and (2 * 1100mL) wash to the solid that leaches, and at 100 ℃ and reduce under the pressure of 1mm HgA it is implemented drying, provide with 2.6 ℃ toluene
8(recording purity by HPLC is 98.2% for 1654.9g, 96.9% productive rate, wherein comprises the main impurity debrominate of about 0.9 mole of %
8).
Example 6: preparation N-(4-chloro-phenyl-)-N '-(4-methoxyl group-3-(4 '-bromo-1 '-methyl isophthalic acid H-pyrazoles-5 '-yl) phenyl) urea (9).
Right
7(101.9g, 0.3612 mole) is dissolved in the solution of toluene (1020mL) and implements stirring, and passes dean stark trap and under atmospheric pressure implement to reflux under nitrogen, to remove 5mL water.When phlegma become fully clarification, in dean stark trap, no longer include water and gather after, toluene solution is cooled to envrionment temperature, implement to filter removing a small amount of undissolved residue, and it be back in the reaction flask.Under nitrogen to through azeotropic drying
7Toluene solution cool off with water-bath and when stirring, divide rough three equal parts to add the isocyanic acid 4-chloro-phenyl-ester (55.5g, 0.3614 mole) of solid form with overhead stirrer.Interpolation through about two minutes first part causes the temperature of described reaction mixture to be increased to 23.5 ℃ from 18.5 ℃.When described reaction mixture has been cooled to 18.7 ℃, added second section isocyanic acid 4-chloro-phenyl-ester through about 5 minutes, the temperature of reaction mixture does not change.During adding first part, one second liquid phase (lower floor's liquid phase) is separated in mutually from toluene.Finish back-page interpolation after 5 minutes, this second liquid phase (lower floor's liquid phase) beginning crystallization causes the temperature of described reaction mixture to be increased to 22.5 ℃ after next 10 minutes.Under envrionment temperature and nitrogen,, then it is implemented suction filtration with described reaction mixture restir 2.5 hours.With toluene (150mL, envrionment temperature) to the solid that leaches implement washing and through 28 hours at 97 ℃ and be reduced to and under the pressure of 1mm HgA it implemented dryly, provide
9(150.08g, 95.3% productive rate comprise passing through of 1.0 moles of %
1H-NMR and LC/MS analyze the observable impurity debrominate that only has
9).
The application's case is correlated with for the 60/555th, No. 626 with the U.S. Provisional Patent Application case of filing an application on March 23rd, 2004, and described temporary patent application case all is incorporated herein with way of reference.
Except that embodiment as herein described, those of skill in the art should be easy to envision various modification of the present invention according to above-mentioned explaination in the industry.The present invention also desire is covered by these modifications in the scope of the claim of enclosing.Each reference that the present invention quoted all is incorporated herein by reference.
Claims (50)
1. the method for preparation formula 8 compounds:
Described method comprises
Make formula 7 compounds
With isocyanic acid 2,4 difluorobenzene ester
React for some time under the condition that is fit to described formula 8 compounds of formation, wherein said being reflected in the organic solvent that comprises toluene implemented.
2. the method for claim 1, wherein before the described reaction described formula 7 compound dissolutions are being formed solution in described organic solvent, wherein said organic solvent comprises toluene, and described solution is refluxed for some time can removing at least in part.
3. method as claimed in claim 2, the amount that wherein is present in the water in the described solution after described backflow is by volume less than 0.01%.
4. method as claimed in claim 2, the amount that wherein is present in the water in the described solution after described backflow is by volume less than 0.005%.
5. method as claimed in claim 2, the amount that wherein is present in the water in the described solution after described backflow is by volume less than 0.001%.
6. the method for claim 1, wherein said reaction is implemented at low temperatures.
7. method as claimed in claim 6, wherein said low temperature are 10 to 20 ℃.
8. the method for claim 1, wherein said reaction is to implement in inert atmosphere.
9. the method for claim 1 wherein is added into isocyanic acid 2,4 difluorobenzene ester in the solution that comprises described formula 7 compounds.
10. method as claimed in claim 9, wherein said interpolation are by a part enforcement.
11. the method for claim 1 is wherein added isocyanic acid 2,4 difluorobenzene ester with the mole excessive with respect to the amount of formula 7.
12. the method for claim 1, wherein said formula 7 compounds are the method preparations by may further comprise the steps: make formula 6 compounds
Under the condition that is fit to described formula 7 compounds of formation, react for some time with removing protective material.
13. method as claimed in claim 12, the wherein said protective material that goes is an alkali.
14. method as claimed in claim 12, the wherein said protective material that goes comprises oxyhydroxide.
15. method as claimed in claim 12, the wherein said protective material that goes comprises sodium hydroxide.
16. method as claimed in claim 12, wherein said is to implement in organic solvent with going protectant reaction.
17. method as claimed in claim 16, wherein said organic solvent comprises alcohol.
18. method as claimed in claim 16, wherein said organic solvent comprises methyl alcohol.
19. method as claimed in claim 12, wherein said is to implement under reflux temperature with going protectant reaction.
20. method as claimed in claim 12, wherein said with go protectant reaction to cause to form with respect to the amount of formula 7 compounds formula (IIb) compound less than 5 moles of %:
R wherein
2Be CH
3, R
4Be OCH
3, and R
5Be H when occurring, and wherein when described reaction begins, described formula 6 compounds comprise in fact not formula 5 compounds of detectable amount at every turn:
。
21. method as claimed in claim 20, wherein said and formula (IIb) compound that goes protectant reaction to cause to form less than 3 moles of %.
22. method as claimed in claim 12, wherein said formula 6 compounds are the method preparations by may further comprise the steps: make formula 5 compounds
Under the condition that is fit to described formula 6 compounds of generation, react for some time with bromide reagent.
23. method as claimed in claim 22, wherein said bromide reagent comprises N-bromosuccinimide.
24. method as claimed in claim 22, wherein said and reaction bromide reagent is to implement in organic solvent.
25. method as claimed in claim 24, wherein said organic solvent comprises alcohol.
26. method as claimed in claim 24, wherein said organic solvent comprises methyl alcohol.
27. method as claimed in claim 22, wherein said and reaction bromide reagent are at room temperature or are lower than under the room temperature and implement.
28. method as claimed in claim 22, wherein said formula 5 compounds are the method preparations by may further comprise the steps: make formula 4 compounds
With NH
2NH-CH
3Under the condition that is fit to described formula 5 compounds of generation, react for some time.
29. method as claimed in claim 28, wherein said and NH
2NH-CH
3Reaction be in the presence of organic solvent, to implement.
30. method as claimed in claim 29, wherein said organic solvent comprises alcohol.
31. method as claimed in claim 29, wherein said organic solvent comprises methyl alcohol.
32. method as claimed in claim 28, wherein said and NH
2NH-CH
3Reaction be in the presence of acid, to implement.
33. method as claimed in claim 32, wherein said acid comprises mineral acid.
34. method as claimed in claim 32, wherein said acid comprises HCl.
35. method as claimed in claim 28 wherein is added into described formula 4 compounds and comprises NH
2NH-CH
3And in the solution of HCl.
36. method as claimed in claim 28, wherein said and NH
2NH-CH
3The further production of reaction (Va) compound:
Wherein said formula (Va) compound generates with more described formula 5 compounds amount still less,
R wherein
2Be CH
3, R
4Be OCH
3, R
NFor H, Pr are-C (O) Me, and R
5When occurring H at every turn.
37. method as claimed in claim 36, the mol ratio of wherein said formula 5 compounds and formula (Va) compound is greater than 2.
38. method as claimed in claim 36, the mol ratio of wherein said formula 5 compounds and formula (Va) compound is greater than 5.
39. method as claimed in claim 28, wherein said and NH
2NH-CH
3Reaction be under-10 to 30 ℃ temperature, to implement.
40. method as claimed in claim 28, wherein said formula 4 compounds are the method preparations by may further comprise the steps: make formula 3 compounds
With dimethylformamide dimethyl acetal
Under the condition that is fit to described formula 4 compounds of generation, react for some time.
41. method as claimed in claim 40, wherein said and reaction dimethylformamide dimethyl acetal is to implement in solvent.
42. method as claimed in claim 41, wherein said solvent comprises alcohol.
43. method as claimed in claim 41, wherein said solvent comprises ethanol.
44. method as claimed in claim 40, wherein said and reaction dimethylformamide dimethyl acetal is to implement under reflux temperature.
45. method as claimed in claim 40 wherein is added into dimethylformamide dimethyl acetal in the mixture of described formula 3 compounds and solvent.
46. method as claimed in claim 40, wherein dimethylformamide dimethyl acetal provides with the mole excessive with respect to the amount of formula 3 compounds.
47. method as claimed in claim 46, wherein the mol ratio of dimethylformamide dimethyl acetal and described formula 3 compounds is 1.5 to 3.
48. formula 4 compounds:
49. formula 5 compounds:
50. formula 6 compounds:
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US55562604P | 2004-03-23 | 2004-03-23 | |
| US60/555,626 | 2004-03-23 | ||
| PCT/US2004/023880 WO2005103011A1 (en) | 2004-03-23 | 2004-07-21 | Processes for preparing substituted n-aryl-n’-[3-(1h-pyrazol-5-yl) phenyl] ureas and intermediates thereof |
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| CN1926114A CN1926114A (en) | 2007-03-07 |
| CN1926114B true CN1926114B (en) | 2011-08-24 |
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| CN2004800425186A Expired - Fee Related CN1926114B (en) | 2004-03-23 | 2004-07-21 | Processes for preparing substituted N-aryl-N'-[3-(1H-pyrazol-5-yl) phenyl] ureas and intermediates thereof |
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| US (1) | US7812176B2 (en) |
| EP (1) | EP1727803B3 (en) |
| CN (1) | CN1926114B (en) |
| AT (1) | ATE548353T1 (en) |
| CA (1) | CA2559038C (en) |
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Also Published As
| Publication number | Publication date |
|---|---|
| HK1092152A1 (en) | 2007-02-02 |
| CN1926114A (en) | 2007-03-07 |
| US20070293685A1 (en) | 2007-12-20 |
| EP1727803A1 (en) | 2006-12-06 |
| CA2559038C (en) | 2013-09-10 |
| US7812176B2 (en) | 2010-10-12 |
| ATE548353T1 (en) | 2012-03-15 |
| CA2559038A1 (en) | 2005-11-03 |
| EP1727803B1 (en) | 2012-03-07 |
| WO2005103011A1 (en) | 2005-11-03 |
| EP1727803B3 (en) | 2014-04-23 |
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